Respondent’s Exhibit MM

~Eric Fombonne, M.D.F.R.C.Ps chCanada Research Chair in Child PsychiatryProfessor of Psychiatry McGill UniversityDirector of the Department of Psychiatry at the Montreal Children’s Hospital

~round and Experience

1. I am a Professor of Psychiatry and the Head of the Division of Child

Psychiatry of McGill University. I am also the Director of the Department of Psychiatry and

Director of the Autism Spectrum Program at the Montreal Children’s Hospital.

2. I received my medical degree in 1978 from University of Paris V, and won a

special distinction for my MD thesis. I received a Masters Certificate in Biostatistic Methods and

Human Physiology in 1977. I have a specialization in General Psychiatry and Child and

Adolescent Psychiatry.

3. I was a Reader in Epidemiological Child Psychiatry at the University of

London (a unique position created in recognition of my epidemiologic expertise in the area of child

psychiatry). I have taught epidemiological methodology to physicians and public health workers.

Over the course of my career, I have designed, executed, analyzed, and published dozens of

epidemiologic studies involving autism and other child psychiatric disorders. All of the studies

were funded by either public health organizations or private charitable not-for-profit organizations.

None of my research has been funded by private industry or pharmaceutical companies.

4. I have had a long-standing professional interest in autism. My research

career started in 1984 with the planning of the first populationTbased epidemiological survey of

child psychiatric disorders ever conducted in France. In 1986, I was invited to consult with other

professionals (mostly clinicians) to develop an autism research program in France. I subsequently

obtained a grant to conduct a large multicenter study of autistic adolescents and developmentally-

delayed controls. I also obtained a separate grant with a U.K. group of investigators to examine the

neuropsychology of autism. In London, in 1988, I acquired clinical expertise in the assessment and

diagnosis of subjects with autism, being one of the first to obtain training on the newly devised

diagnostic measure, the Autism Diagnostic Interview (ADI). In 1990, I provided autism expertise

in a survey conducted by an Institut National de la Santd et de la Recherche M~dicale (INSERM)

team, which led to the publication of the first autism survey in France in 1992 (Fombonne & du

Mazaubrun, 1992).

5. In 1993, I accepted an academic position at the Maudsley Hospital and

Ins’titute of Psychiatry in London, and worked with the Medical Research Council (MR(;) Child

Psychiatry Unit headed by Professor Michael Rutter. My research activities focused on autism

including: an adoption study of children with autism, a family study of autism, the first molecular

genetic investigation of autism, epidemiological surveys of autism, and studies of the putative links

between autism and the measles-mumps-rubella (MMR) immunization. I also conducted research

on child and adolescent depression and headed a clinical service for depressed youths in addition to

my clinical activities in autism. I served as a consultant to the Department of Health and the

Medical Research Council in the U.K. to review the hypothesis of links between measles-mumps-

rubella (MMR) immunization and autism.

6. From 1991 to 1994, I was a member of a small study group of international

scholars assembled by Professor Rutter on behalf of the Academia Eur0peae to review the evidence

for secular ch~inges in the incidence ofpsychosocial disorders in young people. This work

culminated in a book that assessed the evidence for increasing rates of problems such as crime,

juvenile delinquency, depression, eating disorders, suicide, and alcohol and drug use in young

people in various countries in the second half of the twentieth century (Rutter & Smith, 1995).

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During those years, I gained expertise in reviewing hypotheses on changes over time in the

incidence of disorders. In addition to the two chapters authored in the Rutter and Smith book

(Fombonne 1995a and 1995b), I published several scientific articles on the topic (i.e., Fombonne,

1995c; Fombonne, 1996a; Fombonne, 1998a & 1998b). In 1996, I published on the issue of secular

changes in the incidence or prevalence of autism in an editorial column (Fombonne, 1996b). I was

the first investigator in the field of autism to empirically address the issue, using epidemiological

data, to test whether or not autism was on the rise (Fombonne et al., 1997b). At the end of my stay

in the U.K., I published two papers that have been regarded as very influential for the epidemiology

of autism and for the hypothesis of links between MMR immunization and regressive autism

(Chakrabarti & Fombonne, 2001; Fombonne & Chakrabarti, 2001c).

7. In 2001, I moved to the Montreal Children’s Hospital, McGill University, in

Canada. I have been specially appointed to the Canada Research Chair in Child Psychiatry. I have

developed an independent research program on autism at McGill. I have been funded recently to

conduct several studies of autism including a study of the exposure to environmental

neurotoxicants (including mercury), a new molecular genetic study of autism, an epidemiological

survey of autism in Montreal, a randomized clinical trial of an intervention to promote language

development in young preschoolers with autism, a longitudinal. Study of autistic preschool children,

and a study of the outcome of autism in adult life. I am the Principal Investigator of the only

Canadian team funded in the new genetic research initiative funded by the U.S.-based Simons

Foundation. I am the Principal Investigator on a large Canadian grant to train and attract to autism

research young trainees from all disciplines and, as part of this training program, I have organized

the first summer school on autism since 2004 at McGill University; this program continues and has

already funded 32 fellows to boost research capacity on autism in Canada.

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8. I have been directly involved in the design, execution, and analysis of 10

different epidemiological surveys of autism (2 in France, 3 in the U.K., 3 in Canada, 1 in South

Korea, and 1 in Australia) and I have been providing consultancies on surveys conducted by other

research groups, including three in the U.S. - the Centers for Disease Control and Prevention

(CDC) in Atlanta, GA, the University of Utah, and the M.I.N.D. Institute in Sacramento, CA. With

the support of Autism Speaks, I am currently consulting with public health authorities in Mexico to

design the first epidemiological study of autism there. I am also planning the first survey of autism

in Belarussia using data already collected on over 13,000 children in a Canadian-funded research

study.

9. Throughout the years, I have maintained my clinical practice. When I was at

the Maudsley Hospital, I was the leading consultant of the autism service, a national team that

received referrals from throughout the U.K. for complex cases. My current clinical practice

involves assessing, treating, and following up autistic patients of all ages; I also consult about the

assessment and management of complex psychiatric cases referred to me by colleagues, especially

in the field of affective disorders. Currently, I have ongoing clinical activities and every week

assess new patients with suspected pervasive developmental disorders (PDDs) from birth to adult

life. I assess over 150 new cases per year and carry a caseload of about 250 autistic children

currently.

10. Over the years I have been an advocate for children with autism and their

families. I have volunteered my time by attending and lecturin~ at parent-run advocacy groups for

the treatment and the development of services for autistic children in different countries,

11. I have trained many professionals and residents in the assessment of patients

with autism. I am a teacher for trainees in child psychiatry and other mental health professionals. I

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spend a considerable amount of time giving seminars for residents, presentations and academic

grand rounds at various University hospitals, and providing lectures for the community. I have a

specific training expertise in assessment tools used in the field of autism research. I organize

regular training seminars and workshops to train my clinical and research staff and professionals in

the community in up-to-date and modern techniques used in the field of PDDs.

12. I am a regular reviewer of research papers on autism for numerous journals

and, from 1994 to 2003, I was the associate editor of the Journal of Autism and Developmental

Disorders, a leading journal in the field of autism. I am on the Advisory Editorial Board of the new

scientific journal Autism Research that was launched in 2008 by the International Society for

Autism Research (ISAR).

13. I have served as a consultant to various agencies such as the CDC, the

Institute of Medicine (IOM) in Washington, DC, the American Academy of Pediatrics (AAP), the

Medical Research Council in the U.K., the M.I.N.D. Institute, and the National Institutes of Health

(NIH) in Bethesda, MD. I was a permanent reviewer for one scientific review committee of the

National Institute of Mental Health for the period 2002-2006. I am on the Advisory Board of

various organizations such as the Canadian Autism Intervention Research Network (CAIRN) and

the UC Davis Center for Children’s Environmental Health, and I am a member of the Advisory

Committee set up by the NIH, NICHD and NIMH to oversee the autism research activities funded

in the U.S. as part of the CPEA and STAART Centres (now Autism Centers of Excellence). ! was

a member of the Planning Committee of a special Neurosciences Seminar on autism and

environmental risk factors, organized by the IOM on April 18-19, 2007. I was an invited

consultant to an American Psychiatric Association workshop in Sacramento, CA (3-5 February

2008) to set up the future research agenda for autism research and advice on changes in diagnostic

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concepts and criteria that will appear in 2010 in the new (fifth) edition of the Diagnostic and

Statistical Manual of Mental Disorders.

14. I have published over 170 scientific articles in peer-reviewed journals, four

books, and 33 chapters.

15. Further information on my background and qualifications is given in my

curriculum vitae.

Standard for My ~Afinions

16. On the basis of my review of the literature and my knowledge, skill,

education, experience, research, and training in the fields of Autism and Epidemiology, I have

formed the following opinions to a reasonable degree of medical certainty:

17. It is my opinion, to a reasonable degree of scientific and medical certainty,

that thimerosal-containing vaccines do not cause autism. The claim that there is an autism

epidemic c, aused by vaccinations is unfounded, without reliable scientific support, and is not

generally accepted in the autism research community. There is no reliable scientific or medical

basis to support a conclusion that there is an association or a causal relationship between

thimerosal-containing vaccines and autism spectrum disorders, and the evidence favors rejection of

such a causal relationship.

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Pervasive Developmental Disorders

18. Autism Spectrum Disorders (ASDs) are referred to as PDDs in the two

current diagnostic Classification systems, the Diagnostic & Statistical Manual, 4th Edition, Text

Revision (DSM-IV) of the American Psychiatric Association and the International Classification of

Diseases, 10th Edition (ICD-IO) of the World Health Organization. "Autism" is a term that refers

to ASDs and PDDs and also is often used as a shorthand reference to one of the specific ASDs,

Autistic Disorder.

19.

hundreds of years.

Autism is a disorder that has been recognized, although not named, for

It clearly pre-dates the use of thimerosal in vaccines and other biologicals. Uta

Frith, an autism researcher in the U.K., has described the autistic characteristics of Brother Juniper,

a 12th Century monk, and the Wild Boy of Aveyron, who was found in the wild in France in the

18th Century (Frith, 2003). Childhood Disintegrative Disorder, a rare form of severe regressive

autism, was first described in 1908 by Heller as "dementia infantilis" (Heller, 1908). The European

medical literature, as early as 1926, contained detailed clinical descriptions of children with

symptom patterns typical of those described later as Asperger’s Disorder (Wolff, 1996). The name

"autism" was first coined in 1943 by Leo Kanner of Johns Hopkins, who reported on his

observations of 11 children whom he was seeing with significant social and language deficits and

impairment of imaginative play.

20. PDDs are a class of disorders characterized by severe impairments in three

developmental domains: communication skills (both language and non-verbal communication);

social interaction and reciprocity; and unusual pattern of play, interests, activities, and behaviors.

The particular behaviors that index the developmental deficits in the three domains outlined above

vary from one individual to the other, within an individual according to age, and according to the

overall level of functioning or of intelligence.

21. The DSM-IV provides diagnostic criteria for disorders that are usually first

diagnosed during infancy and childhood; it is the standard used to diagnose PDDs in many parts of

the world, including in both the U.S. and Canada. It classifies and provides the diagnostic criteria

for five Pervasive Developmental Disorders - (1) Autistic Disorder, (2) Rett’s Disorder, (3)

Childhood Disintegrative Disorder (CDD), (4) Asperger’s Disorder, and (5) Pervasive

Developmental Disorder Not Otherwise Specified (PDDNOS). These PDDs constitute what are

referred to as Autism Spectrum Disorders. For consistency and convention, throughout this report I

use the term Autism Spectrum Disorder (or ASD) to refer to these PDDs (except for Rett’s

Disorder, as discussed below).

22. Rett’s Disorder affects mostly females and is due to a defect on the MECP2

gene localized on the chromosome X (Amir et al., 1999). Because its phenomenology, causes, and

outcome are different from the other PDDs, Rett’s Disorder is not included in studies of autistic

samples.

23.

(Fombonne, 2002a).

Childhood disintegrative disorder (CDD) represents a very rare form of ASD

It is a severe form of autism that differs from Autistic Disorder by its

developmental trajectory. In CDD, there is evidence of unambiguous normal development up to at

least age 2. After thi,s period of normal development, and on average close to 3 years 0f age

(Volkmar, 1992), there is a profound regression and loss of skills in at least two domains (language,

social skills and adaptive behavior, bowel and bladder contro!, play, and motor skills) that

ultimately leads to a clinical picture similar to severe autism.

24. Asperger’s Disorder presents the same abnormalities of Autistic Disorder for~

the social interactive skills and the patterns of abnormal play and interests, but differs insofar as

language development proceeds largely within normal limits (i.e., the child uses phrase speech by

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age 3). In addition, with Asperger’s Disorder, there is no mental retardation, whereas

approximately 70% of patients with Autistic Disorder are also mentally retarded.

25. The diagnostic criteria for Autistic Disorder consist of a detailed listing of

social, communicative, and behavioral symptoms. The diagnosis of Autistic Disorder requires

deficits in each of three domains of early development: (1) impairment in social interaction (lack of

eye contact, impaired peer relationships, lack of spontaneous seeking of shared experiences, and of

social reciprocity); (2) impairment in communication (delay of spoken language, impairment of

conversational skills, use of repetitive and idiosyncratic language, lack of imaginative play); and

(3) restricted, repetitive, and stereotyped behaviors (restricted patterns of interest, inflexible

routines and rituals, stereotypical motor mannerisms, preoccupation with parts of objects).

Impairments within these three areas must be evidenced with an onset of symptoms prior to age 3.

If these criteria are met, then the clinician must still rule out Rett’s and CDD before a diagnosis of

Autistic Disorder can be made.

26. Autistic Disorder is the appropriate diagnosis for children who present with

all the typical symptoms of autism. It is used when the child meets full diagnostic criteria as

outlined in major nosographies (classifications), such as the DSM-IV or ICD-10. The DSM-IV

requires that the child show at least six out of a list of twelve possible symptoms. There must be

evidence of two symptoms involving social development, and at least one symptom involving each

of the domains of communication malfunction and abnormal pattern of play. The first symptoms

must be identified as having existed before the third birthday.

27. The next diagnostic category in the DSM-IV is PDDNOS. PDDNOS is also

referred to as atypical autism. This category is used for those children who present the autistic

abnormalities but fall short of full diagnostic criteria for autism. For example, the child may have

9

the same symptoms as another child with Autistic Disorder, but the parents may have detected the

first developmental abnormality only after age three.

28. The diagnostic assessment of ASD is made by reviewing the current

behaviors of an individual and reviewing his past developmental history. The diagnosis usually

involves a direct assessment of the child using standardized tasks and activities designed to elicit

the particular communication, social, and play deficits of children with ASDs. This is usually

complemented by a detailed developmental interview using the parent as the source of information

to elicit information about past and current symptoms, as seen in different contexts and over time.

An ASD diagnosis is made solely on the basis of behavioral and developmental abnormalities;

there are no biological markers or medical tests that can confirm or disprove the diagnosis.

29. There is a high degree of consensus among world experts on the definition

and the procedures required to diagnose and assess subjects with Autistic Disorder (Volkmar et al.,

1994; Filipek et al., 2000), and the reliability of the diagnosis (i.e., the extent to which two

independent clinicians would arrive at the same diagnostic conclusion) is high for the ASDs.

30. Although classification systems identify separate diagnostic categories or

groupings within each class of ASD, there is increasing evidence that the boundaries and

differences among these diagnostic categories are somewhat arbitrary and merely represent

variations in intensity of the same core underlying deficits. In ongoing molecular genetic studies in

which families are ascertained because at least two relatives are affected with an ASD, most

research groups have identified families where the two relatives affected within the same family

have different diagnoses (e.g., Autistic Disorder and Asperger’s Disorder, or PDDNOS and

Asperger’s Disorder, etc.). The fact that ASD subtypes cluster in families indicates that ASDs have

common causal mechanisms.

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31. There appears to be no association with social class, as ASDs are found at all

social class levels and occur in families with different educational backgrounds. It also appears that

autism can occur in different ethnic groups; in all countries where autism has been investigated,

cases have been found (Fombonne, 2003a, 2005a, and 2005b). There is no evidence that the rates

of autism differ across countries or nations, with perhaps one exception amongst the Inuit

population of Northern Canada where a preliminary study failed to find any case of autism in a

population of approximately 5,000 children (Fombonne et al., 2006a).

Onset of Autistic Disorder

32. The onset of Autistic Disorder is difficult to measure. The diagnostic

criterion of the DSM-IV is that "onset" of some abnormalities must occur before the third birthday.

Rather than being a direct measure of the onset of the disorder, this criterion refers to the time at

which parents become aware that the development of their child is not entirely right. Age of

parental recognition is influenced by several factors that pertain to the child’s disorder, as well as to

other contextual factors. For example, children who have autism and severe mental retardation are

more likely to be identified as abnormal by their parents at an earlier age because the child fails

very early in his development to achieve some important milestones (i.e., sitting or walking) that

are hard to miss. Other studies have also shown that when the autistic child is not the parents’ first-

born, the parents’ recognition of autistic symptoms occurs earlier, as they have gained more

experience about normal childhood development through their first child; they know what to

expect; and they are more quick to recognize deviance or delay in the development of their

subsequent child (DeGiacomo & Fomborme, 1998). As in many disorders in medicine (such as

cancer), it is therefore likely that the onset of the disorder occurs long before the age at which the

first symptoms become manifest to parental eyes.

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33. Early manifestations of autism have been extensively studied in the last 20

years. Analyses of home videos and of first birthday parties have allowed early developmental

abnormalities to be identified at the end of the first year of life, which characterize children later

diagnosed with autism, and that separate them from both typically developing peers and non-

autistic mentally retarded controls (Osterling et al., 2002; Werner et al., 2000; Werner & Dawson,

2005; Baranek, 1999; Mars et al., 1998). At 12 months of age, children later diagnosed with autism

were more abnormal than control children in such behavior as looking at faces, orientation to their

name, communicative babbling, and poorer joint attention behavior. Prospective studies of

individual cases (Dawson et ai., 2000; Klin et al., 2004) and of high-risk (younger siblings of

autistic children) infants have since confirmed that abnormalities can be detected at 12 months of

age in eye contact and visual tracking, social orienting, imitation, social interest and smiling,

fixation of objects, and motor and language skills (Zwaigenbaum et al., 2005; Landa & Garrett-

Mayer, 2006). These abnormalities may or may not be recognized by parents at the time.

~e~ressive Autism

34. While some autistic children fail to acquire skills expected as part of normal

development (i.e., social smile), or display abnormal behaviors (i.e., hand and finger mannerisms),

typically between the age of 9 and 18 months (Carter et al., 1998), there is a subgroup of children

with ASDs who appear to develop relatively normally up to a certain age and then lose skills,

specifically the use of words to communicate, that they had gained before the first autistic

symptoms developed. The loss of words to communicate often co-occurs with the emergence of

social deficits that may be less easy to observe and recall. This phenomenon, now called

"regressive autism" and referred to as such in the rest of the report, occurs in about 20% of children

with either an Autistic Disorder or a PDDNOS diagnosis (Lord et al., 2004; Fombonne &

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Chakrabarti, 2001). This regressive pattern appears to be highly specific to ASDs, as it is not

reported in children who have developmental delays without autism or language disorders (Lord et

al., 2004).

35. When the onset of autism occurs with a regressive pattern, parents have tried

to identify events that occurred immediately before the regression in order to explain it. This is

understandable, but temporal correlation does not mean causation. The emergence of the first

symptoms of autism is variable but occurs, by definition, before 3 years of age, and in the majority

of cases during the second year of life. For example, in a large study comparing autistic children

with and without regression, the mean age of autistic symptom onset was 16.9 and 13.7 months,

respectively (Richler et al., 2006). In another recent study of toddlers diagnosed with ASDs, the

mean age of symptom recognition in 51 children with Autistic Disorder was 14.7 months

(Chawarska et al., 2007). Vaccinations are given to children between birth and two years of age.

Therefore, the age of onset of autism and the date of vaccinations are constrained by an overlapping

time window. Thus, it follows that, in many children, the onset of first autistic symptoms will occur

just after their routine vaccinations, or in the weeks that follow.

36. It is noteworthy that studies of parental beliefs have shown that parents of

children with regressive autism are more likely to believe that vaccinations, or similar causes, are

responsible for their child’s autism (Lingam et al., 2003; Woo et al., 2004). In previous studies

(when vaccinations were not under consideration), parents attributed the onset of autistic symptoms

to various other events such as the birth of a younger sibling, moving house, mother’s

hospitalization, etc. (Kobayashi et al., 1998). Parents, and more generally, human beings, have a

tendency to seek coherence in their life by ascribing personal events to external causes, even when

there is no scientific basis for these ’correlations’.

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37. It has often been assumed that ’regressive autism’ occurs in children whose

development was normal up to the point of the loss of skills. In fact, the loss of skills does not

mean that the child’s development was entirely normal before the regression. Recent studies have

suggested that most children with regressive autism displayed subtle developmental abnormalities

long before the regression occurred (Luyster et al., 2005; Rogers, 2004). For example, in a U.S.

study of 13 sites funded by the NIH, an evaluation of 163 autistic children with regression showed

that 72% were not developing normally before the regression (Richler et al., 2006). Thus,

abnormal development can be documented in children with ’regressive autism’ before the

regression occurs even though the parents are unaware of it.

38. This was further illustrated in a recent study documenting clearly abnormal

patterns of head growth before the first birthday in a sample of autistic children. This unusual

acceleration of head growth was seen with similar frequency in the regressive group as compared to

the early-onset group (Webb et al., 2007). This finding again illustrates both the presence of

objective developmental abnormalities before the regression and the similarity between the

regressive and non-regressive groups.

39. Even ifa child’s developmen~ were absolutely normal, as is perhaps the case

in a small subset of children with regressive autism (Werner & Dawson, 2005), the regressive

pattern of behavior does not mean that the cause of the regression is environmental. There are

many genetic diseases that manifest only after a period of normal development, followed by a loss

of function or regression. A close example to Autistic Disorder is Rett’s Disorder, which has an

onset between 6 to 24 months of age following a period of unambiguously normal development.

Rett’s Disorder is due in most cases to a gene defect that has now been identified (Amir et al.,

1999). Another example is that of Huntington’s disease, which is caused by a single gene mutation

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that leads to neurological problems and intellectual deterioration, but often not before the third or

fourth decade of life.

40. It is well established in the behavioral genetic literature that genetic effects

are not necessarily expressed early in life, as genes are programmed to be switched on and off at

different times in the lifespan. Thus, the mere fact of a delayed onset of a disorder does not mean

that the disorder is not genetic in origin. If regressive autism were entirely triggered by

environmental factors, as opposed to only genetic ones, then one would expect the rate of autistic

characteristics (known as the. broad autism phenotype) in relatives of individuals with regressive

autism to be lower than in those of non-regressive individuals. However, this is not the case

because, in both regressive and non-regressive autistic children, there is no difference in the

percentage of their relatives who are also affected with the broad autistic phenotype (Lainhart et al.,

2002).

41. Even if one postulates that regressive autism is triggered by environmental

factors in genetically susceptible individuals, several testable predictions could be made if

thimerosal-containing vaccines were hypothesized to be such an environmental trigger. First, the

parents of children with regressive autism born in the 1990s were exposed to much smaller doses of

thimerosal in vaccines then were their children. Thus, if the above postulate were true, we would

expect to see a lower rate of autism in these older individuals than in relatives of non-regressive

autistic children, but that is not the case (Lainhart et al., 2002). Second, one would expect that the

proportion of regressive autism would have increased over time as a function of increased exposure

to higher doses of thimerosal in vaccines, which has not occurred. Third, the proportion of

regressive autism should be higher in countries like the U.S. where exposure to thimerosal was

higher than in countries (i.e., in Europe) with lower cumulative doses of thimerosal in childhood

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vaccines, which is also not the case. Finally, one would expect to see a decrease in rates of autism

in the population, especially of the regressive form, following discontinuation of use of thimerosal-

containing vaccines, which, again, has not been found (see below).

Autism and Mental Retardation

42. Mental retardation is determined based on performance on verbal and non-

verbal standardized tests of intelligence, for which multiple batteries exist. When children with

ASDs are tested with these standardized IQ tests, about 70% of children with Autistic Disorder

score in the range of mental retardation (IQ is below 70). Subjects with autistic disorder who have

an IQ within the normal range (IQ>70) are often designated as having "high-functioning autism"

(HFA) but HFA represents merely a convenient descriptor and is not a subtype or separate

diagnostic variant of autistic disorder. The rates of mental retardation for PDDNOS are slightly

lower, but no robust estimate exists for this rather heterogeneous group of subjects. By definition

in the DSM-IV, there is no mental retardation associated with Asperger’s Disorder. Children with

ASDs, and especially Autistic Disorder, also tend to have unusual cognitive profiles on these

standardized tests.

Macroce hal in Autism

43. Children with ASDs have abnormal brain development early in their

development. Macrocephaly, or enlarged head circumference, was noted in 5 of the 11 cases

described by Kanner in 1943. This pattern of abnormal head growth was confirmed subsequently,

with about 20% of subjects having macrocephaly or a head circumference that exceeds the 97th

percentile of the distribution of head circumferences in typical children (Fombonne et al., 1999).

Head circumference is closely correlated with brain volume from birth to age three (Bartholomeusz

et al., 2002). Brain neuroimaging (Courchesne et al., 2003; Sparks et al., 2002) and

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neuropathology findings (Bailey et al., 1998) have confirmed patterns of abnormal brain growth,

volume, and weight in autism. Specifically, head circumference is normal at birth; however, at

around 4 months of age, enlargement of the brain becomes noticeable (Redcay & Courchesne,

2005). Increased rate of head growth is now well-documented during the first year of life,

especially during the second semester of the first year, and recent data indicate that the rate of head

growth decelerates in the second year of life where it does not differ from normal head growth

(Dawson et al., 2007). Abnormal head growth precedes and overlaps with the appearance of the

first symptoms of autism, and the deceleration of head growth coincides with a worsening of

autistic symptoms in the second year of life.

44. A recent, large multisite study in the U.S. has examined correlates of

abnormal brain growth in autism, and has investigated the relationship between enlarged head

circumference and height in autistic children compared with normally developing controls

(Lainhart et al., 2006). An increase in the rate of absolute macrocephaly was reported in autistic

children, as has been found in other studies. There was a high correlation between height and head

circumference in both autistic and control subjects. When head circumference was compared to

height, the rate of relative macrocephaly was high in the autistic group, indicating that abnormal

head growth was not accounted for by a growth in height. In fact, a significant discrepancy was

reported between height and head circumference, suggesting that the proportionality between

height and head circumference is distorted in autistic children. Furthermore, there was no

correlation between IQ and head circumference in autistic patients (it was amongst controls).

Delayed onset of language was associated with macrocephaly in the autistic subjects.

45. In a more recent study documenting abnormal head growth during the end of

the first year of life in children later diagnosed with autism, the abnormal pattern of head growth

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occurred at similar frequencies in regressive and non-regressive children (Webb et al., 2007). This

finding is important as it confirms that developmental abnormalities occur in children with

regressive autism much before the loss of skills.

Natural Histor~ and Outcome

46. Follow-up studies have consistently shown that autistic symptoms persist

throughout one’s life span even though marked improvements can sometimes be seen in subjects

with good language and cognitive skills (Eisenberg, 1956; Lotter, 1978; Lockyer and Rutter, 1969;

Howlin et al., 2004). In more recent studies, diagnostic stability has been confirmed from

preschool years to mid-school age for Autistic Disorder (Lord et al., 2006; Charman et al., 2005),

whereas some optimal outcomes have been described in up to 10% of children with an initial

PDDNOS diagnosis - some children lose their initial ASD diagnosis even though they present with

persisting language or attentional difficulties (Fein et al., 2005; Kelley et al., 2006). These findings

are important for two reasons. First, improvement occurs in autism as a function of both biological

maturation and of access to treatments with documented efficacy (i.e., early intensive behavioral

interventions). Thus, interpreting a positive change in an individual child is virtually impossible

because a clinician cannot tease apart the effects of the natural history of the disorder and those of

treatment (and, when multiple treatments are simultaneously administered, no causal inference

about the effect of one treatment regarding the change can be made at all). Second, improvements

have been documented in generations of children exposed to the 1990s’ regimen of thimerosal-

containing vaccines, who were not chelated, thereby suggesting that mercury exposure bears no

relationship with these trajectories.

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Causation of Autistic Disorder and Other ASDs

47. The actual cause of autism in approximately 5-10% of the diagnosed cases

can be determined (Fombonne, 2003a; Rutter et al., 1994). The known causes are enumerated

below and do not include any postnatal environmental factor. Therefore, the cause or causes of the

bulk (90-95%) of autism cases are unknown (idiopathic). Research into the causes has taken

several different paths, including investigations into (a) the role of medical disorders, (b) the role of

genetic factors, and (c) the role of environmental exposures.

48. Guidelines exist to investigate young children diagnosed with Autistic

Disorder or other ASDs to search for genetic or medical causes of autism (Filipek et al., 2000).

49. Tuberose Sclerosis and Fragile X are genetic disorders described in

association with autism.

50. Other rare medical disorders have been described in association with autism

such as phenylketonuria and a few other genetic conditions, particularlythose associated with

chromosome 15 abnormalities (isodicentric chromosome 15 q syndrome, Angelman syndrome).

One medical syndrome, congenital rubella, has been described historically as leading to autistic

syndromes in children affected prenatally by this .infectious agent. These children were studied in

the aftermath of a large U.S. epidemic in the 1960s. While many of them showed autistic traits, the

symptoms subsequently abated (Chess, 1971 and 1977). Currently, congenital rubella does not

account for more than a handful of cases of autism, due to prevention through systematic

vaccination against rubella.

51. Thus, the majority of autism cases are idiopathic (one cannot find a specific

cause or associated medical condition). In those idiopathic cases, there is evidence that genes play

a major role in the development of the disorder.

-19-

52. To date, there are no postnatal environmental factors that have been reliably

demonstrated to play a role in Autistic Disorder or other ASDs.

53. The fact that genes do play a role in autism was established from several sets

of studies. First, family studies have been performed in which the rate of autism in siblings of an

autistic patient (proband) has been calculated. Many such studies demonstrate that once a family

has a child with an ASD, there is a rate of about 3% for another sibling to be affected with Autistic

Disorder, and an additional 3% risk for subsequent offspring to be affected with PPDNOS or

Asperger’s Disorder (Bolton et al., 1994). Current estimates of the sibling recurrence risk are

around 6-15%, depending upon the particular assumptions behind the calculations (Szatmari et al.,

1998; Zwaigenbaum et al., 2005). This is a well-replicated finding, which shows that autism and

other ASDs cluster in families and that the risk of autism in a family is at. least ten times higher than

in the general population.

54. Second, twin studies of autism have compared the concordance rates

between same-sex twin pairs, who share either 50% of their genes (dizygotic (DZ) twins) or 100%

of their genes (monozygotic (MZ) twins). As early as 1977, these twin studies identified a strong

genetic contribution to autism (Folstein & Rutter, 1977). The most accurate and recent estimates

suggest that the concordance rate in MZ pairs is about 70% compared to 0 to 5% in the DZ pairs

(Bailey et al., 1995). This discrepancy between 5% and 70% in DZ and MZ concordance rates

emphasizes the strong influence of genetic factors in autism.

55. Twin studies further indicate that multiple genes, rather than a single gene,

are likely to be involved. Modeling of data from family and twin studies actually suggests that

from 3 to 20 genes may be involved in the susceptibility to an ASD (Pickles et al., 1995; Risch

et al., 1999). Medical geneticists calculate from these twin studies an index of heritability that, in

- 20 -

the case of autism, is above 90% (Bailey et al., 1995.; Szatmari et al., 1998). In most family or twin

studies, investigators have also identified in those twins who appear to be unaffected by autism, or

amongst the unaffected relatives of autism probands, a set of mild developmental abnormalities that

may combine communication and language impairments, social difficulties, unusual interests, and a

tendency for rigid/obsessive behaviors that are conceptually equivalent to the symptoms seen as

part of full-blown autism, but are much milder in intensity. This phenotype is referred to as the

broader phenotype of autism and appears to affect 10 to 20% of first-degree relatives, depending

upon which definition is used (Bolton et al., 1994; Fombonne et al., 1997a). It is believed that

subjects presenting with this broader phenotype carry some, but not all, of the genes involved in

autism.

56. After it was established that genes play a predominant role in the

development of autism, investigators started to explore the genome to identify the genes involved;

I was part of the first international consortium that investigated autism using modern molecular

genetic techniques and, in 1998, published the first results of a genome scan (IMGSAC, 1998). We

followed an affected relative pair approach, whereby we recruited families in several countries in

which two members (usually two siblings) were affected with an ASD. Precise phenotypic

assessments were conducted, and DNA from all family members was extracted from blood

samples. This approach was followed by several research groups.

57. Regions on several chromosomes have now been identified that likely harbor

susceptibility genes for autism. Major research efforts in the molecular genetic studies of autism

are currently ongoing (Muhle et al., 2004; Freitag, 2007). Recently, research groups worldwide

have put their efforts together’ shared samples, and performed new genetic analyses on a much

larger sample of multiplex families (Autism Genome Project, 2007). The results of the genome

-21 -

scan have identified new genes that are likely to be implicated in autism. In addition, the genetic

heterogeneity of autism begins to be better understood because in 10 to 15% of the sample it

appears that copy number variants, small structural changes (either microdeletions or

microduplications) in the DNA that were thus far undetected with conventional cytogenetic

techniques, and that represent de novo mutations, appear to explain autism in a substantial minority

of families. These findings have been replicated in other studies (Sebat et al., 2007; Marshall et al.,

2008) and new deletions and duplications on the short arm of the chromosome 16 have been shown

recently to account for as much as 1% of ASD cases (Weiss et al., 2008). A full understanding of

the causal mechanisms leading to autism is therefore in progress, but much remains to be done to

understand the pathophysiology of this devastating disorder.

58. Few prenatal environmental risk factors have been identified that appear to

increase the risk of autism, including in utero exposure to thalidomide, valproic acid, misoprostol,

and rubella virus infection. All the scientific evidence suggests that the impact of these risk factors

occurs during the early weeks of gestation. Malformations seen in thalidomide exposed patients

indicate that the developmental interference occurs between 20 and 24 days after conception, and

the same is true for valproie acid. For the other exposures (misoprostol, rubella virus infection), the

window of vulnerability occurs during the first 12 weeks of gestation (Rodier & Hyman, 1998;

Rodier, 2004a & 2004b).

59. In addition, cranio-facial dysmorphology and dysfunction of the cranial

nerves are common in children with autism (Rodier, 2000, 2004a & 2004b). When children with

idiopathic autism are compared with unaffected siblings, higher rates of anomalies, such as

posteriorly rotated ears, small feet, and large hands, are observed to occur. Minor physical

anomalies occur at high rates in children with autism. In their review of studies of minor physical

- 22 -

anomalies (MPA), Smalley et al. (1996) concluded that MPAs result from either genetic or

environmental insults that occur in the first trimester of pregnancy and are an indirect measure of

abnormal early fetal development. More recent studies have also found that autistic children were

more likely to have MPAs than normal or sibling controls (Bailey et al., 1995; Rodier et al., 1997).

For example, Miles and Hillman (2000) reported that 20% of their sample of autistic children had

clearly abnormal physical examinations that also correlated with MRI brain abnormalities. Such

dysmorphic conditions or congenital anomalies result from disturbances during embryonic

development; they do not arise postnatally.

60. Also reflecting the early prenatal onset of autism are several neuroanatomical

findings. Several components of the limbic system (a set of forebrain structures involved in

memory and emotionality) show abnormally small and closely packed neurons (Kemper &

Bauman, 2002). Malformations in the neocortex have also been reported (Bailey et al., 1998). In

the cerebellum, a consistent finding is a decrease in the number of Purkinje cells in the cortex;

abnormalities in the size and number of neurons in the deep cerebellar nuclei are also observed.

However, while anomalies in the size of the neurons in the inferior olive of the brain stem also

occur in autism, there is no corresponding loss of these neurons. This destruction of Purkinje cells

without a concomitant loss of olivary neurons indicates that the injury occurred prior to the 28th

week of gestation.1

61. An excessive number of minicolumns has also been described in the brain of

autistic patients. Minicolumns are generated early in gestation by divisions of primordial cells

lining the anterodorsal aspect of the embryonic ventricles, and the total number of minicolumns is

i Because very close neuronal connections between Purkinje cells and neurons in the inferior olive are established by

week 28 of gestation, any loss of Purkinje cells after this point would necessarily result in a loss of olivary neurons. Inautism, what is observed is a loss of Purkinje cells without a corresponding loss of neurons in the inferior olive. It cantherefore be concluded that the injury that results in Purkinje cell destruction occurs prior to the 28th week of gestation(Kemper and Bauman, 2002).

- 23 -

attained in the first 40 days of gestation in primate species (Casanova et al, 2002a, 2002b, & 2003),

again suggesting that an early, prenatal, pathological process is involved in autism.

62. Providing further support for a prenatal onset of brain development

abnormalities, a study by Nelson et al. (2001) showed that, compared to control children, neonatal

concentrations of vasoactive intestinal peptide, calcitonin gene-related peptide, brain-derived

neurotrophic factor and neurotrophin 4/5 were significantly elevated in archived neonatal blood of

children with autistic spectrum disorders or mental retardation without autism. In 99% of children

with autism, levels of at least one of these substances exceeded those of all control children.

Although the results were not specific to autism, they point unequivocally toward prenatal

anomalies in children with autism or intellectual impairments.

Prevalence of ASDs in Human Populations

63. Epidemiology is concerned with the study of the distribution of diseases in

human populations and of the factors that influence it. There are several measures of disease

occurrence used by epidemiologists. Incidence rates refer to the number of new cases (numerator)

of a disease occurring over a specified period of time in those at risk of developing the disease in

the population (denominator, in person x years). Cumulative incidence is the proportion of those

who were fi’ee of the disease at the beginning of the observation period and developed the disease

during that period. Measures of incidence are required to properly estimate morbidity due to a

disease, its possible changes over time, and the risk factors underlying disease status. Prevalence is

a measure used in cross-sectional surveys (there is no passage of time) and reflects the proportion

of subjects in a given population who, at that point in time, suffer from the disease. Most

epidemiological studies of autism have been prevalence, rather than incidence, studies. Ecological

studies compare rates of the disorder and rates of the exposure at a population level without

- 24 -

ascertaining the association between disease and exposure at the individual level. Ecological

studies have been used to evaluate risk of autism in relation to various vaccines.

64. I recently reviewed the epidemiological literature on autism (Fombonne,

2005a, 2005b, 2005c, 2005d, 2005e, & 2006). Overall, forty-two studies published between 1966

and 2004 were identified. Conservative estimates for the current prevalence of Autistic Disorder,

PDDNOS, Asperger’s Disorder, and CDD are: 13/10,000, 20.8/10,000, 2.6/10,000 and 0.2/10,000,

respectively, with a minimum, conservative estimate of 36.6/10,000 for all ASDs. However, six

recent epidemiological surveys yielded higher rates in the 60-70/10,000 range (Baird et al., 2000;

Chakrabarti & Fombonne, 2001; Chakrabarti & Fombonne, 2005; Bertrand et al., 2001; Scott,

2002; Fombonne et al., 2006b). Most of these surveys had specific methodological features, such

as identifying the whole spectrum of ASDs in small populations of young children with very

proactive ascertainment techniques and new assessment methods. The convergence of surveys

around the estimate of 60-70/10,000 for all ASDs combined is striking, especially when derived

from studies with improved methods. In the U.S., the CDC has developed a surveillance program

to monitor the prevalence of ASDs in different U.S. states. The first prevalence estimates from this

epidemiological network were released recently, and they are consistent with the other surveys in

showing an average rate of 67/10,000 in 8-year old U.S. children, in 2000, and an average rate of

66/10,000, in 2002 (Centers for Disease Control and Prevention, 2007a & 2007b). This estimate

(0.6-0.7%) appears to be the best estimate for the prevalence of ASDs currently available.

Is There an ~pidemic of Autism?

65. I first wrote on the subject of whether or not there was a "true" increase in

the number of autism cases (an epidemic) in 1996, and I conducted the first empirical investigation

of this question in 1997. I concluded that there was no evidence for an increase in the incidence of

-25 -

autism because I found no difference in rates of autism in successive birth cohorts of children born

from 1972 to 1985 (Fombonne et al., 1997b). Further studies that I have performed myself, and

systematic reviews of new evidence, have confirmed my initial conclusions (Fombonne, 2003a &

2005b).

66. There are certain methodological standards that have to be maintained when

looking to see if there is an increase of disease or an event over time. For example, if you wanted

to know if the rate of juvenile crime increased in San Antonio, Texas from 1994 to 2004 you would

have to look at the rates in i994 and again in 2004. However, you would have to be sure that you

were comparing apples to apples. A valid comparison of juvenile crime rates could be jeopardized

for at least three reasons: (1) if what we define and count as a crime has changed; (2) if crime

detection and reporting practices have changed; and (3) if changes occurred in the population at

risk for criminal behavior. In this example, an artifactual increase in crime rates could be observed

if new offenses have been added to the list of criminal offenses, or if the police force had been

reinforced or given a strong mandate or incentive to identify and report crime, or if the proportion

of young males increased disproportionately. It would obviously be wrong, under these

circumstances, to claim that a crime epidemic was striking San Antonio.

67. The issue of a so-called epidemic in rates of autism is subject to the same

methodological vulnerabilities. Both prevalence and incidence estimates of autism will be

erroneously inflated if the case definition for autism is broadened and case ascertainment for autism

is improved. In fact, both of those things have occurred.

68. Time trends in rates can therefore only be gauged in investigations that hold

these parameters under strict control over time. This was achieved only in a handful of studies. In

addition, factors such as development of se~wices and support systems for children with autism,

- 26 -

improved awareness by both professionals and lay persons, decreasing age of diagnosis, availability

of information from the Internet, parent support groups, and the removal of the stigma all

contribute to increasing rates of diagnosed ASDs. A few approaches have been employed to

evaluate time trends in rates of autism. These are: referral statistics, comparison of prevalence

studies, and incidence studies.

Rqferral Studies

69. Increasing numbers of children referred to specialist services, or known to

special education registers, have been touted as evidence for an increased incidence of ASDs

(California Department of Developmental Services, 1999, 2002 & 2003).

70. For example, as of January 6, 2003, there were 20,377 cases of autism

identified in the public database (California Department of Developmental Services, 2003). In fact,

this number is much lower than what one would predict based on epidemiological calculations

(Fombonne, 2006). The fact that this number has increased rapidly in the past fifteen years has

been repeatedly used to support the claims of an autism epidemic. Over that period of time,

however, diagnostic practices changed, broader definitions of ASDs were employed, services were

developed, services improved, and autism became subj ect to mandatory reporting (1990) as part of

the U.S. Individuals with Disability Education Act (IDEA). Also contributing to increasing

numbers of ASDs is the practice of"diagnostic substitution," whereby children formerly diagnosed

with a non-ASD (i.e., mental retardation, language disorder) will now receive an ASD diagnosis.

An analysis of the U.S. Department of Education data over time has shown that the increasing use

of the ASD category was paralleled with a decreasing use of the mental retardation category

(Shattuck, 2006). Similarly, data obtained in the U.K. by Jick and Kaye (2003) showed that the

incidence of diagnoses of developmental disorders, including language disorders, decreased by

- 27 -

about the same amount as the incidence of diagnoses of autism in boys born from 1990-1997

increased. Finally, there is evidence that the number of children identified in the school system for

different conditions (i.e., ADHD) has increased, and that the rise is not specific to autism (Gurney

et al., 2003; Shattuck, 2006; Atladottir et al., 2007). On the whole, evidence from these referral

statistics is very weak and cannot be used to determine changes in the incidence of the disorder.

Comparison qf Prevalence Studies

71. Each epidemiological survey of autism possesses unique design features that

differ from study to study. These differences in study design could entirely account for the

different prevalence rates each study generates. Case definition and case ascertainment are at the

heart of these design differences. Time trends in rates of autism are, therefore, difficult to gauge

from comparisons of published prevalence rates (Fombonne, 2005b & 2005c).

72. For example, earlier surveys relied on case definitions and classifications

that tapped a narrow definition of autism. Changes in the classification systems in 1980, 1987, and

1994 progressively broadened the .concept and definitions of autism and other ASDs. Asperger’s

Disorder only appeared as a diagnostic category in the 1994 version of DSM. It would be

inappropriate, therefore, to compare rates from old studies using narrow definitions (Kanner’s

criteria) with more recent surveys that rely on broader based DSM-IV definitions of ASDs. To

illustrate the impact of diagnostic criteria on prevalence rates, one only has to look at the Finnish

study by Kielinen et al. (2000). Kielinen assessed the same children for autism using (1) Kanner’s

criteria, and (2) ICD-10 criteria. He found a two- to three- fold increase in the diagnosis of autism.

These data from the same survey illustrate the huge impact that diagnostic definitions and criteria

have on the rate of prevalence.

-28 -

73. In an editorial for JAMA (Fombonne, 2003), I wrote that one of the least

distorted comparisons over time that could be performed was to contrast the rate of ASDs obtained

by Wing and Gould (1979), in a survey conducted in the mid-1970s in a London borough (about

21/10,000 for the autistic disorder and the triad of impairments), to our current best estimate for

ASDs (60/10,000). This comparison shows a three-fold increase over 30 years, and, as per the

previous point, the increase could clearly be accounted for by changes in diagnostic criteria and

improved ascertainment.

74. It can also be shown that rates in surveys conducted approximately at the

same time can yield very different prevalence estimates with a ten-fold variation in rates or more

(see Table ’Study design impact on prevalence’).

STUDY DESIGN IMPACT ON PREVALENCEU.K. STUDIES

ASDSize Age

Group Method Rate/10,000

Chakrabarti & Siaffordshire 15,500 2½-6½ Intense screening and 62.6Fombonne, 2001 assessmentBaird et al., 2000 South East Thames 16,235 7 Early screening + 57.9

follow-up identificationFombonne et al., 2001England and Wales 10,438 5-15 National household 26.1

survey of psychiatricdisorders

Taylor et al., 1999 North Thames 490,000 0-16 Administrative records 10.1

U.S. STUDIESBertrand et al., 2001 Brick Township, NJ 8,896 3-10 Multiple sources of 67

ascertainmentSturmey & James, Texas 3,564,577 6-18 Educational services 162001CDER, 1999 California 3,215,000 4-9 Educational services 15Hillman et al., 2000 Missouri -.- 5-9 Educational services 4.8

75. The only explanation for such variability in rates lies in the differences in

methodologies employed in each of these surveys because the studies were conducted at the same

time, in the same country, and of children of similar age (Fombonne, 2003 & 2005).

- 29 -

76. Typically, surveys that rely on passive, administrative methods to count

subjects yield much lower rates than those studies that employ more comprehensive and systematic

ascertainment procedures. As it is, therefore, very difficult to compare meaningfully rates between

recent surveys performed with different designs, it is even less valid to compare rates of studies

conducted at different historical periods.

77. In some instances, it has been possible to compare prevalence rates in

successive birth cohorts surveyed with rigorously identical methods for case definition and case

ascertainment. Such comparisons reveal no increase in the prevalence of ASDs. We performed

two separate surveys looking for ASDs in children born between 1992 and 1995, and between 1996

and 1998, in Staffordshire, in the U.K.

STAFFORDSHIRE SURVEYS

92-95 cohort 96-98 cohort Combined samples

N=15,500 N=10,903 N=26,403

N P N P N P 95%ci

Autistic Disorder 26 16.8 24 22.0 50 18.9 14.1-25.0

PDDNOS 56 36.1 27 24.8 83 31.4 25.0-39.0

Asperger’s 13 8.4 12 11.0 25 9.5 6.1-14.0

CDD 1 0.7 1 0.9 2 0.8 0.1-2.7

All ASD 96~ 61.9 64 58.7 160 60.6 51.6-70.7

1One girl with Rett’s Syndrome has been excludedN = number P = prevalence rate per 10,000 Chakrabarti & Fombonne (2005)

78. The prevalence for all ASDs was comparable in the two birth samples and

not statistically different in the two surveys, suggesting no upward trend in overall rates of ASDs

during the studies’ time interval. In another analysis of pooled survey data on 735,000 children

from studies that strictly relied on comparable methods, age-specific prevalence rates showed no

upward trend in cohorts born from 1972 to 1985 (Fombonne et al., 1997b). If there had been an

- 30-

increase in the incidence of autism during that period, the prevalence in the most recently born

children should have been higher than that amongst the older children.

79. A recent analysis of special educational disability from Minnesota showed a

sixteen-fold increase in the number of children identified with an ASD from 1991-1992 to 2001-

2002 (Gurney et al., 2003). However, in this study, it was not possible to adjust for changes in

diagnoses or improved case ascertainment. In addition, the increase was not specific to autism

because during the same period, an increase of 50% was observed for all disability categories

(except severe mental handicap), especially for the category including ADHD. Gurney et al.

(2003) further argued that this phenomenon coincided closely with the inclusion of ASDs in the

federal Individual with Disabilities Educational Act (IDEA) funding and reporting mechanism in

the U.S. The addition of high functioning autistics also accounts for some of the increase (Eagle,

2004). Similar conclusions were obtained by Shattuck (2006) in an. analysis of trends in ASD

categories in the U.S. using the Department of Education data for all 50 states.

Incidence Studies

80. Several recent studies provided ASD estimates (Powell et al., 2000; Kaye et

al., 2001; Smeeth et al., 2004; Barbaresi et al., 2005). All showed an upward trend. For example,

in the largest study of 1410 subjects, we found a ten-fold increase in the rate of first recorded

diagnoses of ASDs in United Kingdom general practice medical records from 1988-1992 to 2000-

2001 (Smeeth et al., 2004). The increase was more marked for ASDs other than autism, but the

increase in autism was also obvious. However, none of these studies could control for confounding

due tO changes over time in diagnostic criteria, improved awareness, and service availability.

81. A more recent study deriving from the Danish National Psychiatric register

provided cumulative incidence data for autism and ASDs together with data on Tourette syndrome,

-31 -

hyperkinetic disorder, and obsessive-compulsive disorder (OCD) (Atladottir et al., 2007). The

population size of children born between 1990 and 1999 was 669,995 children. Outcome data for

each birth cohort were collected from 1995 through 1999, a period in which ICD-10 codes were in

use and both inpatient and outpatient data were included in the National register. Statistically

significant increases were reported for successive birth cohorts for all disorders except OCD. The

study was uninformative about the possible causes of these trends but clearly showed that the

increase over time was not specific to autism or ASDs, but rather applied to a range of

neurodevelopmental disorders.

82. The available epidemiological evidence does not support the hypothesis that

the incidence of autism has increased for reasons other than changes in diagnostic practices and

improved detection. As it stands now, the recent upward trend in rates of prevalence cannot be

directly attributed to an increase in the incidence of the disorder. There is evidence that changes in

diagnostic criteria, diagnostic substitution, decreasing age at diagnosis, changes in the policies for

special education, and the increasing availability of services are responsible for the higher

prevalence figures. Most of the existing epidemiological data are inadequate to test properly

hypotheses on changes in the incidence of autism in human populations. The studies that could "

more adequately control for alternative explanations have failed to detect an upward trend in rates

of ASDs.

- 32 -

Have Rates of Rel~ressive Autism Increased?

83. Regression in autism has been known for a long time, and it is not a new

phenomenon. There are several examples in the early psychiatric literature of regressive patterns of

autism being described by various clinicians and investigators worldwide.

CltntealClinicalCtinical

Cl~nical O~ = 17~)Kobavashi and Murata,

D~eriptton of the Regression

~,¢elopmenta[ ~tback that i:ncluded 313

Spff~dx,i’~ture 1~ lasting over 6 o*~.~ ~month~

~tback in development 25 O~back In devd0pm~nt 500~troN’~t,,’~ sh~ft with ~pc~:h 22.4

d.i~pFea r ~ neeNormal d~vdopment ~otlo~m~ by 20,6

1~ of ,,,vord,iinte~*~t for a

~ An appendix corttainin~ clinical dea:riptions of [o~s or" ~k:ills and :regr~ston h~am this em’lier lit~ratu~ can L~ obtainedaufl~or ub~n mqu, e~t.

84. In the earlier studies, the rates of regressive autism in autistic series ranged

from 20% to 50% (see Table 1 above from Fombonne and Chakrabarti, 2001c; Rogers, 2004).

These rates and descriptions were established before any concerns about immunizations were raised

and when the cumulative exposure of infants to thimerosal was much lower than in recent years.

To give specific examples, in 1964, Wolff and Chess made the following clinical observations

about regression:

Case 4 Began to speak before 12 months. Then after a separation from his mother he stoppedspeaking and did not say another word until 2½.

Case 5 Began to speak at 17 months but at 2 he lost all speech.

Case 6 Said single words at 12 months, smiled at people and reached out towards them. At 2he lost all communicative speech and only repeated television commercials. Hisexpression became blank.

Case 8 Began to speak at 10 months but stopped at 14 months and lost contact with people.

Case 9 At 21 months, following the birth of his brother, he no longer said the 4 words he hadpreviously spoken and began to spend most of his time looking at magazines. He didnot begin to speak again until he was 4.

(Wolff & Chess, 1964)

- 33 -

85. With the more stringent and reliable definitions used in recent research, the

best estimate that we have for any regression or loss of skills in the developmental course of

children with ASD is about 20% (Fombonne & Chakrabarti, 2001c; Lord et al., 2004). Specific

investigations have been carried out recently to assess whether or not the frequency of regressive

autism has increased over time.

86. We tested this hypothesis using data from our British survey of autism in

Staffordshire and a clinical sample from the Maudsley Hospital (London, U.K.) (Fombonne &

Chakrabarti, 2001c). Both samples had been assessed by independent clinicians and researchers

who were unaware at the time of collection of data that this study would be performed. In both

studies, parents of diagnosed children were interviewed with a standardized diagnostic measure, the

Autism Diagnostic Interview (ADI), that has become the standard in our field. The Maudsley

Hospital sample comprised subjects who were born mostly in the 1970s. The Staffordshire sample

was born between 1992 and 1995. Regression in the developmental course of subjects from the

two samples was defined by parental answers to specific questions about regression in language or

other skills included in the ADI. The rates of reported regression were 18.4% in the Maudsley

Hospital sample, and 15.6% in the Staffordshire sample, a non-significant (p>.70) difference that

does not support the hypothesis of an increase in regressive autism over a 20-year period.

87. In the U.K., Taylor et al. (2002) examined regression in a sample of 473

children born between 1979 and 1998. Regression was reported in 118 children (25% of the

sample). No significant trend was found by year 0fbirth (OR=0.98; p=0.50) during the 20-year

time period of the study. In other words, the proportion of regressive autism remained constant

during this interval.

- 34 -

88. In the validation exercise we conducted for the U.K. case-control study of

MMR and autism (Smeeth et al., 2004), we evaluated 178 medical records of autistic children born

between 1973 and 1997 and rated the presence/absence of regression in their development. We

then compared the proportion of regressive cases of autism over 5 five-year intervals spanning the

years 1973 to 1997. A test for trend showed no significant (p>.75) change in the proportion of

cases with regression (Fombonne et al., 2004).

89. . In Japan, Uchiyama et al. (2007) studied 904 children diagnosed with ASD

and born between 1976 and 1999. The study was designed to test the relationship between MMR

exposure and regressive autism. The rates of regression were similar in the pre-MMR cohorts

(34.0%), in the MMR generation (35.6%), and in the post-MMR cohorts (40.0%). No difference

was found when comparing the rate of regression in the MMR generation to that of all birth cohorts

unexposed to the vaccination (35.6% vs 38.9%; OR=0.87; 95%CI: 0.64-1.18, p=.36). The authors

rightly concluded that their findings disproved the hypothesis that MMR causes regression in ASD.

Irrespective of the MMR question, the value of this study is that it adds to the evidence of stability

over time in the proportion of regressive autism cases.

90. Regression in autism was described a long time ago. Studies that have

assessed trends over time in regressive autism have not shown an increase in regressive autism.

Childhood Vaccines and Autism

91. Since 1998, concerns have been raised about childhood vaccines and the risk

of autism. Two separate hypotheses have been advanced. One hypothesis relates to the measles

component of the triple vaccine MMR. The other relates to thimerosal (a substance containing

ethylmercury) that has been used in most other childhood vaccines since 1930. The hypotheses are

independent because MMR never contained thimerosal (it is a live attenuated vaccine). Reviews

- 35 -

by independent scientific committees or authors have consistently concluded that the link between

MMR and autism was not supported by the studies, leading to the rejection of this hypothesis

(IOM, 2004; Medical Research Council, 2001; Demicheli et al., 2005; Taylor, 2006; Madsen &

Vestergaard, 2004; DeStefano & Thompson; 2004; D’Souza et al., 2006; Afzal et al., 2006; Baird

et al., 2008). I now review epidemiological studies that are relevant to the hypothesis of an

increased risk of ASD following exposure to thimerosal-containing vaccines.

Epidemiology of Thimerosal-Containin~ Vaccines and Autism

92. Several epidemiological studies have tested the hypothesis that the risk of

ASD in children is increased as a function of the amount of thimerosal included in childhood

vaccines. The studies have employed different designs, including cohort studies, case-control

studies, and ecological studies. These studies are reviewed in the following sections.

93. In Denmark, Hviid et al. (2003) compared the incidence rates of autism and

ASD amongst over 460,000 children born between 1990 and 1996, using the national psychiatric

and immunization registers. The sample was ascertained over the whole country and yielded a

large sample of 440 cases with autism in particular, and 787 cases of ASDs in general. In

Denmark, the vaccine schedule involved three immunizations at 5 weeks, 9 weeks, and 10 months

of age with the first dose containing 50tag of thimerosal and the following two doses each

containing 100~g of thimerosal. Thus, as thimerosal contains about 50% ethylmercury, the total

exposure at 10 months of age was 125~g of ethylmercury. Of hotel at 3 months of age, Danish

children were exposed to 75~.tg of ethylmercury., which is comparable to the exposure of children in

the U.S. in the 1990s. The recruitment of an unexposed group in that study was facilitated by the.

fact that, in Denmark, thimerosal was discontinued in vaccine production in 1992. Therefore, the

unexposed cohort is less likely to represent a biased or atypical group of children who are not

- 36-

following the immunization schedule because they are at risk of some sort of neurodevelopmental

disorder.

94. For autism, after adjusting for calendar period and age, the incidence rate

ratio was 0.85 (95%CI: 0.60-1.20) for autism, and 1.12 (95% CI: 0.88-1.43) for ASDs. This shows

no increased risk following vaccination with any thimerosal-containing vaccine as compared to that

following vaccination with 0nly thimerosal-free vaccines. When results were adjusted for age,

calendar period, gender, birthplace, birth weight, Apgar scores, gestational age, maternal age at

birth, and maternal country of birth, the conclusions remained unchanged. The authors also

conducted an analysis to test different levels of ethylmercury exposure. There was no evidence of a

dose response with increasing ethylmercury exposure for either autism or ASD. Thus, the rates

ratio for any increase of 25~.tg in the level of ethylmercury exposure were 0.98 (95% CI: 0.90-1.06)

for autism, and 1.03 (95% CI: 0.98-1.09) for ASDs. Various potential sources of biases (to test for

misclassification on exposur~ in 1992, for diagnostic heterogeneity, or for missing values) were

considered in subsequent analyses that did not show they were likely to have resulted in these

negative findings. In addition, a time trend analysis showed statistically significant increases in

age-adjusted risk ratios for autism (RR=l.24; 95% CI: 1.17-1.31) and for ASDs (RR=1.21; 95%

CI: 1.16-1.27) during the study period. As new data from outpatient clinics were added to the

national database in the course of the study, the authors tested whether or not these changes in

ascertainment could have affected the results. They conducted an additional time trend analysis

restricting the sample to a time period (1995-2000) where no change occurred in the registry. The

time trends analysis in this restricted sample showed rigorously comparable and statistically

significant increases in age-adjusted risk ratios for autism (RR=1.24; 95% CI: 1.16-1.32) and for

- 37 -

ASDs (RR=1.20; 95% CI: 1.13-1.26). The study was population-based, well-powered, and

published in the renowned scientific journal, JAMA.

95. Two other controlled epidemiological studies were performed in the U.K. in

similarly large population-based samples (Andrews et al., 2004; Heron et al., 2004). The first

study, by Andrews et al. (2004), used data from approximately 110,000 children born between

1988 and 1997 and recorded in the General Practice Research Database (GPRD). To be eligible to

participate in the study, children had to be followed from birth until age 2 or more and could not

have any pre-, peri-, or post-natal conditions or negative developmental outcomes in the first six

months of life. Exposure to thimerosal was ascertained from the electronic records using

information about DTP and DT vaccines received by the study subjects. A validation study was

conducted on a small sample recruited from 152 general practices and 80% of the GPRD diagnoses

for neurodevelopmental disorders were confirmed by independent inspection of medical records.

96. The hazard ratios for cumulative exposure to thimerosal by 3, 4or 6 months

of age were all non-significant. More specifically, after adjustment on date of birth and gender, the

hazard ratios for autism were 0.89 (95% CI: 0.65-1.21) and 0.94 (95%CI: 0.73-1.21) for receiving

an additional vaccine dose by 3 and 4 months of age, respectively. An analysis of thimerosal

exposure using a composite continuous ]ndex yielded an adjusted hazard ratio of 0.99 (95%CI:

0.88-1.12), showing no dose response relationship. The Andrews et al. (2004) study was published

in the very respected journal, Pediatrics.

97. Heron et al. (2004) used a prospective cohort of about 13,000 young

children born in Avon followed from birth to school age. The exposure to thimerosal Was

calculated at 3, 4, and 6 months of age on children who were exposed to the normal U,K.

immunization schedule. On a range of outcomes collected over time between 6 and 91 months of

-38 -

age, no deleterious effect of thimerosal was reported. Although ASD as a specific outcome was not

examined, there was no association between thimerosal exposure and a statement of special

educational needs, a category that would ordinarily comprise ASD children in the U.K. (see Heron

et al., 2004, page 578, paragraph on Special Needs). The adjusted odds ratios for the likelihood of

a Local Educational Authority statement at 91 months of age were nonsignificant at 3 months of

age (OR=0.78, 95%CI: 0.60-1.02), at 4 months of age (OR=0.83, 95%CI: 0.67-1.04), and also

when the cumulative exposure to thimerosal was examined as a continuous variable (OR=0.87,

95%CI: 0.78-0.96). In fact, the last results indicated a significant result indicative of a protective

effect of higher thimerosal exposure at 6 months for a statement of special needs. This unexpected

finding applied to four of the five other significant results and the authors also noted that a majority

of analyses indicated trends towards a protective effect of thimerosal exposure.

98. In the U.S., Verstraeten et al. (2003) used data from the Vaccine Safety

Datalink (VSD) to conduct a retrospective cohort study funded by the CDC. The study was

conducted in two phases: the first phase screened two HMOs to identify potential associations that

would then be confirmed in the second phase, using another HMO to replicate the findings. In the

first phase, two HMOs (A and B) were enrolled in the study. Children had to be born and

continuously enrolled in the HMOs during their first year of life and had to have received at least

two polio vaccines during that first year.

serious maternal illnesses were excluded.

Infants with low birth weight, congenital disorders, or

The cumulative exposure to thimerosal was evaluated at

1, 3, and 7 months of life at ages where exposure relative to body weight is at its peak. The

cumulative dose, therefore, ranged from i2.5~g in the first month up to a maximum of 187.5~xg at 6

or 7 months. A validation study of medical records was conducted showing accuracy of the

diagnosis of autism in 92.3% of the cases in HMO A, and in 81.3% of the cases in HMO B.

-39r

99. HMO A had a relatively small population of 13,337 subjects and had too few

cases (N=21) of autism to be analyzed according to a priori decisions made by the authors, HMO

B had 202 autism cases (out of a sample size of 110,833), and the hazard ratios for 12.5

increases in ethylmercury exposure at one, three, and seven months of age were 1.16 (95% CI:

0.78-1.71), 1.06 (95% CI: 0.88-1.28), and 1.00 (95% CI: 0.90-1.09), respectively. Categorical

analyses of cumulative exposure to ethylmercury also showed no effect at age 3 and 7 months.

100. In the second phase of this study, a third HMO was used to replicate any

significant findings from phase one, including stammering, Attention Deficit Disorder, speech and

language delay, tics, and sleep disorders. HMO C had a cohort size of 16,717 children and none of

the 15 analyses conducted on the five neurodevelopmental outcomes were significant with respect

to cumulative thimerosal exposures at 1, 3, and 7 months, examined as a continuous variable.

101. Concerns have been raised about differences in resUlts obtained at different

stages of the study before its final publication. However, it is common in the conduct of

epidemiological studies to go through different iterations and obtain intermediate findings that may

change as new analyses are conduc~ed, and new confounder variables are identified that need to be

considered in modeling the data. One concern about the Verstraeten et al. (2003) study pertained to

pooling of the data from the two HMOs, A and B, during phase one. However, a reanalysis of this

study by petitioners’ experts has shown that the original conclusions of Verstraeten et al. were

entirely valid (Austin & Lally report, 2006).

102. In the U.K., Jick and Kaye (2004) conducted a case-control study in which

they examined records of children from the GPRD born between 1990 and 1998. ASD cases

(N=122) were matched to controls (N=587) on gender, age, general practice, and index date of

registration. The proportion of cases and controls exposed to three thimerosal-containing vaccine

- 40 -

doses by age six-months was comparable (92% vs 88%, respectively; OR = 1.6; 95% CI: 0.7-3.3).

This case-control study found no association between ASD and thimerosal-containing vaccines.

103. Madsen et al. (2003) conducted an ecologic study ofthimerosal-containing

vaccines and ASD using the Danish National Register of psychiatric hospitalizations since 1971,

and all outpatient psychiatric visits since 1995. All children between age 2 and 10 years with a

diagnosis of autism received between 1971 and 2000 were included, giving a total sample of 956

children with autism over the study interval. Due to changes in the immunization schedule in

Denmark, children born between 1961 and 1970 in that study had received 200gg of ethylmercury

by age 15 months. During the period 1970 to 1992, they had received 125~tg of ethylmercury by 10

months of age. Thimerosal was then removed from vaccines in Denmark in 1992, allowing for a

comparison of rates of ASD before and after the use of thimerosal-containing vaccines. The

incidence rates were relatively stable from 1970 to 1990. Thereafter, the incidence increased in all

age groups until 1999. The change in incidence occurred around 1990 at a time when no change

occurred in the vaccine immunization schedule. Similarly, the discontinuation of thimerosal in

1992 had no impact on the ascending trend in rates of autism: incidence rates had started to

increase in 1990 and 1991, and kept increasing at the same pace after discontinuation of thimerosal.

To examine the impact of adding outpatient data in 1995, the authors restricted their analysis to

inpatient data only and again reported the same trend of regular increase of rates of ASD from 1990

to the end of the study period (although the specific data were not included in the article).

104. Stehr-Green et al. (2003) conducted a similar ecologic study ofthimerosal-

containing vaccines and autism in Sweden and Denmark during the 1980s and 1990s, which they

compared to trends from California public services. In Sweden, thimerosal was discontinued in

vaccines in 1993, and in Denmark, in 1992. Swedish data were limited to inpatient statistics, but

-41 -

the recording system did not change during the study period (unlike in Denmark). In California,

exposure to thimerosal increased during the study period. Interestingly, the incidence rates of ASD

in the 3 datasets began to rise slowly in the mid-to-late 1980s and then increased more steadily in

the 1990s. When thimerosal-containing vaccines were discontinued in Denmark and Sweden, there

was no deceleration in the rate of increased incidence of ASD in those two countries. In fact, the

increase continued or accelerated after the discontinuation of thimerosal in vaccines. The findings

suggest that the similar patterns of increased incidence in the three datasets have no relationship

with thimerosal exposure, but rather reflect changes in diagnostic practices, and availability and

access to sel-cices.

105. We have conducted another ecological study, in Quebec, where thimerosal in

vaccines was removed altogether in 1996 due to the development of a new penta-vaccine that

combined the polio vaccine with other vaccines (and, as a result, thimerosal could no longer be

employed in the production of this vaccine). In an epidemiological study, we estimated the rates of

autism for successive birth cohorts from 1987 to 1998. Children were selected because they

attended one the schools of an Anglophone schoolboard of West Montreal in October 2003, from

kindergarten through grade eleven. The children with an ASD diagnosis were classified as special

need students identified through a specific administrative code. Exposure to thimerosal was

estimated by calculating the cumulative dose of ethylmercury received by the children from birth to

age three, if they followed the official immunization schedule. The rates of autism increased

linearly during the whole period by about 10% each year. During the study period, the amount of

ethylmercury included in vaccines varied from a medium level (100 to 125 txg) from 1987 to 1991,

to a high level (200 ~tg) from 1992 to 1995, and to a nil level from 1996 and beyond. As can be

- 42 -

judged by a visual inspection of the data (see Figure in paragraph 106), and by statistical modeling

of the data, we found no association between thimerosal and the risk of autism.

106. We conducted several analyses to test for the effect of misclassification on

exposure or diagnostic status and found the results to be robust. This study adds to the existing

body of evidence on the subject in showing: a) that changes in levels of ethylmercury exposure

10o~

8o

6o

40

20

-225

~150

-t25

100

Grade 1! 10 9 8 7 6 5 4 3 2 1 KYear ofblrth 87 88 89 90 91 92 93 94 95 96 97 98

FIGURE 2Nrth cohort prevalence rat~s and eth),~mercui,~ exposure, Dottedlines take into account the additional ethylmercury exposure be-cause~fa mass vaccination c,3mpaign against meningitis (see

from medium (European countries) to high (U.S.) levels had no impact on the rates of autism and

their trend over time; and b) that, like other discontinuation studies (see Stehr-Green, 2003; Madsen

et al., 2003; Schechter & Grether, 2008), removal ofthimerosal from vaccines does not result in

any deflection in the rates or trends of autism and ASDs. Of note is the fact that the level of

thimerosal included in vaccines in Quebec, from 1992 to 1995, was comparable to that used in the

U.S. at the same time.

107. Recently, Schechter and Grether (2008) published .results from an analysis of

prevalence by age and birth cohort of children with autism who were active status clients of the

California DDS from January 1, 1995, through March 31, 2007. As thimerosal-containing vaccines

- 43 -

were discontinued in the U.S. in 2001, it had been predicted by proponents of the autism-thimerosal

hypothesis that rates of autism should fall as a result of the discontinuation of thimerosal, a trend

that Geier and Geier (2006a) claimed to have detected. The study precisely tested this prediction

with a sound set of methods and analyses, and Schechter and Grether showed that the time trends in

California provided no support to the thimerosal/autism hypothesis. Specifically, they found that

for children born between 1989 and 2003, the prevalence of autism increased consistently during

the periods in which exposure to thimerosal decreased. Moreover, since 2004, the period at which

a decline in autism should have been observed if thimerosal contributed to the cause of autism, in

children ages three to five years, the prevalence of autism in fact increased at a steadier pace than

that for other developmental disabilities (see Figure below). This study adds a consistently

negative result to previously published discontinuation studies. Its particular significance is the fact

that the study’s data came from the California database that proponents of the thimerosal/autism

hypothesis abundantly used in support of their claim (Fombonne, 2008). In addition, like the

Canadian study (Fombonne et al., 2006b), and in contrast to European studies, the California study

examines the effects of discontinuation of thimerosal in populations of children who were exposed

previously to presumably "high" levels of thimerosal.

- 44 -

10- -- Tc~ Di3S~li,/e highs --- Auliern DEtb’l~e births---- Tc~ DD~)opul~lim .... Auliern or’~’pepulaik~ ...... ~

~J’ e~firfla~es ~tirnat~s ’ ~ .,~ ~ :~ "11,::.:~:.~-

O"

Qu~rl:~r

~kjure ~. Pte,~len~e ot ~ ~11sm 8rid ton 0ali]ornl~ ~p~riment oi’ De~eloprnenl~l ~ep~’lee~ IDD&) clienL erlrNlmmt repo~ted b~ the OO~ lot ~,hiklre~ aged g to 5ye~r~ b~ re~tln0 quarter (0), Jam~r3~4, I gg,~, through l’~1~rch ~I, 200~, Pre~,alen~ is e~Im~ted b~ dMdil~g the number of ~c41ve ~t0.~,~ childrell wiLh autism~

b~ the number ol l~,e, blMhs In C~’~li10r~l(~ for each qLerterl~ cohor~ flora I¢~5g to 200~ (~lid ~nd do~ed lin~l and Lhe n~mber ol children e~rn~Led I~ r~Ide ingalll~orni~ for each quarter from le~ Lo 2004w (l~el~ed lin~},

108. Although not examining the association between autism and thimerosal

exposure per se, another published study recently conducted by the CDC is worth mentioning

(Thompson et al., 2007). There, the authors included 1,047 children in the U.S., ages seven to ten

years, selected from four HMOs participating in the VSD, and performed direct testing of 42

neurological outcomes, blind to exposure status. Because some of these outcomes (i.e., speech and

language measures, intellectual and cognitive functioning) could be regarded as component parts of

the ASD phenotype, the study’s results are relevant here. Further, this study is the first to examine

the neurodevelopmental outcomes in childhood, in humans, following earlier exposure to

thimerosal-containing vaccines. Exposure to thimerosal was calculated by pre-natal exposure

through the mother’s treatment with immune globulins or her receipt of thimerosal-containing

vaccines, and postnatally through computerized immunization records supplemented by other

information sources. Thimerosal doses were related to the weight of the child at the time of

vaccine administration. Three exposure windows were created (prenatal exposure, birth-to-7

months, birth- to-28 days). There was no consistent pattern of results, with few associations

- 45 -

reaching the level of statistical significance, but being of small magnitude and representing an

equal number of positive or negative effects. Thus, this well-powered study provides no support

for an increased incidence of negative neurodevelopmental outcomes as a result of thimerosal

exposure amongst school age American children exposed to the immunization schedule in place in

the U.S. in the 1990s.

109. In line with Thompson et al. (2007) regarding the lack of an association

between risk of neurodevelopmental outcomes and prenatal exposure to thimerosal, Miles and

Takahashi (2007) studied 214 mothers of children with an ASD with complete records, including

blood group status and RhIg exposure. In mothers of children with autism, Rh(-) status was no

more frequent than in the general population. Similarly, exposure to antepartum RhIg, preserved

with thimerosal, was not higher for children with autism, and pregnancies were no more likely to be

Rh incompatible. Importantly, this was also true for children with a regressive onset and for autism

subgroups defined by other behavioral characteristics that included gender, IQ, head circumference,

or dysmorphology. These findings invalidate the results obtained by Geier and Geier (2007) on a

limited and biased sample.

110. To address claims raised by petitioners’ experts, it is also useful to extract

from the published epidemiological studies data and results that directly challenge assumptions

made by those experts. Some epidemiological studies have been criticized because the overall

levels of exposure to ethylmercury were lower in European countries than in the U.S. in the 1990s.

This, however, is not always a correct assumptionl For example, Madsen et al. (2003) comment on

the levels of ethylmercury received by Danish children born from 1961 through 1970: the

cumulative dose of ethylmercury was 200txg by 15 months of age. It is clear from the incidence

data shown in the 1970s, in their Figure 1, that no ’epidemic’ of autism resulted in the birth cohorts

- 46 -

exposed to these high levels. Second, to consider as uninformative studies that have a limited range

of exposure would be appropriate if some form of threshold effect (by which the exposure increases

the risk of the outcome only after a certain ’dose’ has been reached) had been demonstrated in other

studies. No such demonstration exists, however. In fact, all dose-response analyses conducted thus

far, including studies in which the exposure range included higher levels (i.e., Verstraeten et al.,

2003), have consistently failed to show such a dose-response relationship. Third, whichever

conflicting theories are embraced by petitioners’ experts (the 10% clearly regressive subgroup, or

the thimerosal-induced increase in rates of all ASDs), they both lead to predictions of a detectable

decline in rates of autism following discontinuation of thimerosal use in vaccine production.. There

are now four studies that have all failed to document such a trend, including two (Fombonne et al.,

2006b; Schechter & Grether, 2008) in which thimerosal exposure was at its highest levels before

discontinuation. Fourth, rates of regressive autism have not changed over time, and rates of

regression are comparable in countries with moderate exposure to ethylmercury (U.K.: Fombonne

and Chakrabarti, 2001 c; Fombonne et al., 2004) to those countries with higher exposure levels

(Lord et al., 2004).

111. Other ecological studies have been conducted that showed a correlation

between rising autism rates and increased use of thimerosal in childhood vaccines (Geier & Geier,

2003, 2004, 2005, 2006a & b; Blaxill, unpublished). None of these studies was controlled, and

their methods have been reviewed and criticized by an ad hoc scientific committee appointed by

the IOM. Detailed descriptions of the methodological flaws in these studies can be found in the

IOM’s report (2004). These studies were considered to be uninformative and added nothing to the

discussion on determining causality.

- 47 -

112. Other ecological studies have examined patterns of associations between

environmental levels of mercury and rates of autism (Palmer et al., 2006; Windham et al., 2006).

Of note, these two studies did not test specifically the effects of exposure to ethylmercury

(contained in thimerosal) and, therefore, are not directly informative to an examination of the

putative association between thimerosal-containing vaccines and ASDs. However, because they

feported correlations between environmental mercury and rates of autism, they are briefly

discussed here.

113. Palmer et al. (2006) reported positive correlations between the amount of

mercury released in the environment and rates of children with autism who were enrolled in special

education classes. The strongest associations in that study were between rates of autism and

urban!rural residence, illustrating the notorious difficulty in controlling for confounding variables

in this type of ecological study. Further, the rates of autism in children enrolled in Texas schools,

in 2001, from kindergarten to grade twelve were correlated with environmental releases of mercury

in 2001. Obviously, children included in this study were born sometime between 1983 and 1995,

and autism became manifest in these children between 1986 and 1998 (as it is a diagnostic

requirement that symptoms occur before age three). Thus, this study reports on correlations

between a disease and an exposure that occurred after disease onset in study subjects. Besides

indicating a poor study design, this flaw also points to the general difficulty in inferring causality

from ecological correlations.

114. The Windham et al. (2006) study suffers from .the same limitations. There,

environmental exposures were measured two years after the birth of the children included in the

sample. In addition, the risk of autism was slightly increased in relation to several highly

intercorrelated exposures to environmental substances that included, in addition to mercury,

-48 -

cadmium, nickel, and chlorinated solvents. This lack of specificity, the absence of a dose-response

relationship, and several other limitations a.cknowledged by the authors, make this study non

contributory to an examination of the role of mercury exposure as a risk factor for ASDs.

115. Reviews of this body of evidence by independent authors (Parker et al.,

2004; Rutter, 2005; Doja & Roberts, 2006; Hviid, 2006; Taylor, 2006; DeStefano, 2007) and

scientific committees (IOM, 2004; National Advisory Committee on Immunizations, 2007) have

concluded that the evidence favoured the rejection of the hypothesis of a link between thimerosal-

containing vaccines and the development of autism in children.

116. In sum, epidemiological evidence derived from well-conducted studies, by

different groups of investigators, in different countries, has consistently failed to document an

increased risk of ASD in relation to exposure to thimerosal, either as a categorical or a continuous

exposure. All public health and scientific reviews of this question have rej ected this hypothesis.

What is striking is the consistent replication of negative findings across investigations that

otherwise differed with respect to their sample sizes and selection, design, countries, investigators,

and other critical variables.

Dr Greenland’s Report

117. I have read Dr Sander Greenland’s expert report dated August 13, 2007. The

following comments are in response to several statements and opinions that he expressed in that

report.

118. Having reviewed the epidemiologic literature on mercury-containing

vaccines (MCV) and autism, Dr. Greenland, at the beginning and in the conclusion of his report,

rejects the association: (see page 1, Introduction: "while the epidemiologic literature to date has not

detected an association of MCV with autism in general or autistic spectrum disorders..."; and page

- 49 -

16, point 8, Conclusion section: "the brief overview given above supports the idea that the

association of MCV with autism is small or non-existent").

119. After Dr Greenland wrote his report, more studies were published that reach

the same conclusion of no causal association. In particular, the study by Schechter and Grether

(2008) discussed above has shown no decline in rates of children with autism enrolled in the public

system of services, in California, after thimerosal was removed from vaccines in the United States.

This ecological study clearly establishes that thimerosal-containing vaccines did not contribute to

the increasing trends since in the 1980s and 1990s in the number of young children diagnosed with

an ASD (Fombonne, 2008).

120. Having concluded that published epidemiologic studies investigating the

association between MCV and autism have been negative, Dr Greenland posits that controlled

epidemiological studies have not tested separately the possibility of an association between MCV

and regressive autism and, therefore, the possibility of a specific association between MCVs and

regressive autism has not been rejected. Dr Greenland calculates that assuming there is a two-fold

increase in the risk of a subtype of autism applicable to 10% of the cases (a subtype he describes as

"clearly regressive autism"), the true association specific to that subtype would remain undetected

in epidemiological studies that do not test specifically for an association between the exposure and

this subtype. Dr Greenland then reviews the results of published epidemiological studies and

concludes that based on the upper limits of the confidence intervals for published risk ratios, a

small association between MC.Vs and clearly regressive autism cannot be entirely ruled out.

According to Dr. Greenland, if such an association existed, it would only lead to a marginal

increase in the risk ratio, and would be diluted by tests that only look for an association between

MCVs and ASDs in general.

-50-

121. Whilst the technicalities of Dr Greenland’s report are accurate, certain

technical aspects merit modification. More substantial conceptual flaws with his opinion are

discussed below.

a. Dr Greenland uses a hypothetical rate of 10% for a subtype of autism that he

contends could be specifically associated with MCVs. However, he provides no

reference in support of this particular figure. Based on recent published data (Lord et al,

2004; Fombonne & Chakrabarti, 2001 c), the frequency of regression in the

developmental course of children later diagnosed with autism can be estimated at around

20%. The most extensive study of the developmental course of children with a regressive

autistic pattern has shown that 72% had abnormal development prior to the regression or

loss of skills (Richler et al, 2006). Therefore, a more accurate figure to use would be 6%

(0.20 x 0.30) to index a group that Dr. Greenland terms "clearly regressive autism."

b. This 6% figure represents an upper bound limit for the true proportion of

children with regressive autism and (apparently) previously normal development. It is

highly probable that the sensitivity of the techniques used to evaluate prior abnormalities

in the development of autistic children prior to their loss of skills is imperfect. This

would lead to an overestimation of the proportion of children with so-called "clearly

regressive autism," who are presumed to be completely normal before the loss of skills.

c. If one admits that the proportion of"clearly regressive autism" cases is 6%

or lower, and if we further assume that this now very small subgroup has a unique and

specific association with MCVs, the dilution bias described by Dr Greenland in his report

would even be greater.

d. Dr Greenland is incorrect when he states that considering a broader category,

such as all ASDs in general, necessarily dilutes a true association between MCVs and

clearly regressive autism. As discussed previously, ASDs include Autistic Disorder,

PDDNOS, Asperger’s Disorder, Rett’s Disorder, and CDDo Autism and PDDNOS

together account for a large majority of ASDs, and regression has been shown to be

comparable in those diagnosed with Autistic Disorder or with PDDNOS (Lord et al,

2004). Accordingly, Dr. Greenland’s comment on page 15 of his report about the

Fombonne et al. (2006b) study is inaccurate. He states that one would expect to find only

-51 -

about a dozen cases of regressive autism. Yet if one looks for regression in both

PDDNOS and autism, one would expect to find much more than twelve cases. In fact,

based on a 20% rate of regression, we would expect to find at least thirty cases of

regressive autism alone.

e. Dr Greenland uses the well-known textbook example of phenylketonuria to

indicate that genetic and environmental factors act together to lead to the onset of a

disorder known to have a genetic origin. I have no disagreement with this example, but

Dr Greenland misses the essential point of my previous testimony (Fombonne, 2007,

paragraphs 37 to 39). I quoted the Lainhart et al. (2002) study, which showed that in both

regressive and non-regressive autistic children, there is no difference in the percentage of

their relatives who are also affected with the broad autistic phenotype. What the study

shows is that the data do not support the hypothesis that regressive autism is a distinct

form of the disorder entirely induced by an enviromnental trigger. Several advocates of

the hypothesis of a mercury-induced autism have posited this hypothesis (one which may

not be embraced by Dr Greenland), but the hypothesis is clearly not consistent with the

evidence. In addition, as already noted above, this and other studies’ results are not

consistent with the hypothesis that thimerosal-containing vaccines act as environmental

triggers of autism in a subgroup of genetically susceptible individuals.

f. In reviewing controlled epidemiological studies, Dr Greenland fails to

emphasize the consistency of risk ratio point estimates obtained by independent

investigators analyzing independent datasets. The two most powered, controlled studies

showed risk ratio estimates for the association between MCVs and ASDs of 0.85 and

0.99: the upper limit of the 95% confidence limits in both studies being 1.20 and 1.12. If

a meta-analysis of these studies were to be conducted, the upper limit would undoubtedly

be closer to 1.0. Although this does not rule out entirely a specific association with a

very small subset of the disorder going undetected, it makes it less likely, especially

considering the conservative assumption of a two-fold increase in the risk taken by Dr

Greenland. This is at variance with claims made by petitioners’ other experts, who

hypothesized a much larger increase in risk. If the increase in risk for a specific subtype

of autism with respect to exposure to MCV was four or five fold, it should have been

detected in these large, controlled epidemiological studies, all of which consistently

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found no association. Nor did these studies find even the beginning of a hint of an

association in a specific subgroup. Following Dr Greenland’s calculations (pages 5 and 6

of his report), I have calculated that if one assumes "clearly regressive autism" occurs in

6% of the cases, and that MCV exposure increases the risk of this subtype five-fold, it

would translate into a risk ratio of 1.24 for ASD in general. This is not consistent with

the two most powered, controlled studies currently available.

g. Dr Greenland cites the Heron et al. (2004) study and finds it uninformative.

That study reported a negative association between the cumulative exposure to

ethylmercury by six months of age and the likelihood of an identification for special

educational needs (adjusted OR = 0.87; 95% CI: 0.78-0.96). Recent research by Golding

(2007) reported on the rate of ASDs in this particular birth cohort, and the investigators

found a prevalence estimate of 62/10,000 that is consistent with recent estimates, and

corresponds to more cases of ASDs (n = 86) than those postulated by Dr Greenland.

122. As there is no empirical data to support his opinion, Dr.Greenland tries to

draw parallels with cancer. He argues that cancer is a broad category of which there are distinct

types or forms (Dr Greenland’s report page 4, section 3). Dr Greenland never defines what he

refers to as (1) a disease category, (2) a distinct type or form, or (3) the criteria that are necessary to

ascertain the distinctiveness of types or forms within a disease category. He uses the example of

cancer (the broad category) within which two types or forms (respiratory system cancers and skin

cancer) have a differential association with smoking. He then goes on to apply this comparison to

the disorder of autism and attempts to dissect the disorder into a non-regressive versus regressive

phenotype; the latter being further subdivided into "clearly regressive autism" and a not-so-clearly-

regressive autism. This analogy between cancer and autism is patently incorrect and is inconsistent

with. biological and medical knowledge. Broncho-pulmonary cancers and skin cancers are different

diseases. In addition to having different symptomatologies, they affect different organs and

different cells; their epidemiology (incidence over time and place, age groups, and gender) is vastly

different; the patho-physiological mechanisms are different; the association with known

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environmental risk exposure (smoking versus sun exposure) are strikingly different; their genetic

backgrounds are most likely different; and the treatments are different, as are the outcomes and the

mortality rates. Broncho-pulmonary cancers and skin cancers represent two different diseases that

are distinct not only in their symptoms or phenomenology, but in their causes, correlates,

treatments and outcomes. Broncho-pulmonary cancers and skin cancers are subsumed into the

same broad category of"cancers" in the same manner as HIV, flu, the common cold, malaria or

streptococcal infection are subsumed into the broad category of "infectious diseases."

123. By contrast, within the category of ASDs, there is no evidence to separate

regressive from non-regressive autism. The main difference is definitional only and relies on

patterns of symptom onset. In classical autism, there is no identifiable loss of skills whereas in

regressive autism, there is an apparent loss of skills that usually occurs during the second year of

life. It was assumed for a long time that the development of children who were losing skills during

their second year of life, and who fit this description of regressive autism, was normal up to the

time of the regression or loss of skills. We now know that is not the case (Lord et al., 2004; Rogers

et al., 2004; Werner & Dawson, 2005; Richler et al., 2006). In fact, in the majority, of cases, the

onset of autistic symptoms occurs prior to the loss of skills, thus blurring the phenomenological

difference between the two clinical presentations. As explained above, recent studies (Richler et

al., 2006) suggest that up to 72% of children with regressive autism have abnormal development

before the loss of skills. As studies become more precise in identifying early symptoms of autism,

this proportion is likely to grow, and it is a true possibility that, with advancing teclmologies, all

children who regress or lose skills Will in fact be shown to have abnormal brain and/or behavioral

development prior to their regression or loss of skills. For example, a similar pattern of abnormal

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head circumference growth between 7 and 10 months of age has now been reported by Webb et al.

(2007), with no difference between regressive and non-regressive autism.

124. Even if one assumes there is a very small subset of children who regress after

apparently normal development, this is not sufficient to establish this phenotype as a distinct ~,

disease, disorder, or syndrome. Medicine in general, and psychiatry in particular, has made

progress in establishing the validity of disorders using a certain number of approaches to

differentiate disorders. The phenomenology of syndromes is usually not a sufficient characteristic

to establish the validity of a psychiatric or developmental disorder (Rutter, 1978). For example,

there is no difference between a spider phobia or a dog phobia: both are simple phobias. Similarly,

Rett’s syndrome can develop in a young girl at age eight months or at age fifteen months, yet no

one would claim that these represent two distinct types of Rett’s syndrome. Rather, one needs to

establish that the two disorders, which can be identified reliably by their clinical descriptions, also

differ with respect to con’elates (i.e., social class, age, gender), age of onset, genetic or social

background, course and natural history, and response to treatment and long-term outcome in order

to establish their distinctiveness. To give two examples, the phenomenology of schizophrenia and

bipolar disorder can be very similar in young children, but the differentiation between these two

syndromes in young people has been made possible by long-term outcome studies or treatment-

response studies. Conversely, depression in children and in adults presents phenomenologically in

different ways, but outcome studies showing a high degree of recurrence of depression as an adult

following a depressive episode in childhood have indicated that these conditions are similar

(Fombonne et al., 2001a). In other words, in order to argue that a syndrome ordisorder represents

similar or different types or forms of a disease, it is not sufficient to rely upon the clinical

~ 55 -

phenomenology or symptom presentation. One needs also to provide other data establishing the

discriminate validity or the uniqueness of the two types or forms.

125. In the case of ASDs, the pattern of regression has been known for over 50

years. All studies that have looked at regressive versus non-regressive autism have failed to

differentiate these two phenotypes for critical features that would support their distinctiveness.

Studies have been performed comparing regressive autism and non-regressive autism on a range of

correlates (i.e., family history of the autism phenotype, Lainhart et al. (2002); symptom severity,

course, and intellectual functioning, Lord et al. (2004), Fombonne & Chakrabarti (2001c); presence

or absence of epilepsy, Tuchman & Rapin (2002); abnormal brain growth during first year of life,

Webb et al. (2007); familiality in multiple and singleton families, Parr et al. (2002); Lainhart et al.

(2002)). The pattern of regressive autism represents only a symptomatic variation in the clinical

presentation that does not carry any other known meaning based on current knowledge. Therefore,

the analogy with broncho-pulmonary cancer and skin cancer is incorrect. A more appropriate

analogy would be to compare regressive and non-regressive autism with different profiles of

symptom onset within broncho-pulmonary cancer, i.e,, one broncho-pulmonary cancer in an

individual might have a slow progressive onset with coughing, repetitive bronchitis and progressive

weight loss, or the same cancer disease could manifest itself suddenly through a massive

pulmonary hemorrhage in an up-to-then asymptomatic individual. In this example, these two

distinct "forms" of broncho-puhnonary cancer only differ in the pattern of first symptoms but not

on other key characteristics of the disease, especially with respect to their cause, prognosis, and

management. There is no need to invoke different etiologies of these two "forms" of broncho-

pulmonary cancer to account for the variability in mode of onset.

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126. As there is no evidence that the slight difference in symptom onset in

regressive autism as opposed to non-regressive autism is a valid subtyping of ASD, and as Dr

Greenland fails to provide any preliminary evidence that exposure to mercury or thimerosal-

containing vaccines increases the risk of autism, one wonders what the starting point of this

hypothesis is. Dr Greenland describes a new form or type of autism that he calls "clearly regressive

autism," but he provides no operational definition for this entity and no demonstration that it can be

reliably and validly measured. Absent such evidence, his recommendation to conduct further

controlled epidemiological studies on this issue (page 16, last paragraph) is meaningless.

127. When several controlled epidemiological studies have failed to reject the null

hypothesis, as has been the case for MCV and autism, it will always be possible to hypothesize that

within the disease phenotype studied, there may be a subgroup (maybe 1% or 1 per 1,000

individuals having this disease), defined by a particular set of clinical or biological characteristics,

who nevertheless ha~,e a uniqu.e, specific association with the exposure under study. For example,

in the case of autism, it is possible not only to stratify any sample by regression status but also by

multiple other phenotypic characteristics, such as bands of intellectual functioning; gender;

presence or absence of epilepsy; presence or absence or macrocephaly; multiple versus singleton

families; family history positive or negative for the broader autism phenotype; language level; and

response to early behavioral intervention. Autism research findings have shown that stratification

using these characteristics is indeed much more meaningful than stratification using regression

status alone. Each sample set of autistic children could possibly be stratified using a combination

of these characteristics that may lead to hundreds of putative, distinct types or forms of autism.

Only then could Dr Greenland or others easily claim that one form (for example children with

autism and epilepsy and macrocephaly and moderate mental retardation) or several forms of the

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disorder have a specific association with the exposure. This, however, would likely lead to an

endless collection of hypotheses or wild speculations about particular "vulnerable" subtypes or

subgroups. Unless the claim for one hypothesized subtype is anchored on preliminary, convincing

biological or epidemiological evidence, epidemiologists would ordinarily not engage to test these

multiple "hypotheses" that are not informed by a defendable disease model or a plausible biological

theory. In fact, the multiple testing associated with such "fishing expeditions" carries the well-

known danger that the testing may give rise to a high number of false positive findings. In

experimental studies (randomized clinical trials), epidemiologists are well aware of these dangers

and require that a small number ofpredefined analyses are conducted on a priori selected primary

and secondary outcome measures in order to test the efficacy of an intervention. In these studies,

the analytical plan is rigorous and concentrates on the plausibly hypothesized relationship between

the intervention and the outcome, and on variables that can be measured reliably. Dr Greenland’s

hypothesis has no preliminary data to demonstrate its plausibility, and it refers to a speculative

phenotype for which no reliable measurement is even available. It would, therefore, be unwise and

in fact, not feasible, to conduct controlled epidemiological studies to test Dr Greenland’s

hypothesis.

128. Dr Greenland points out well-known limitations of ecological studies.

However, ecological studies that evaluate trends over time in a disease during periods where there

is substantial variation in the exposure (especially when the exposure is eliminated) are much less

susceptible to their known biases. For example, three studies conducted independently in three

¯ different countries (Madsen et al. 2004; Fombonne et al., 2006b; Schechter & Grether, 2008) have

all shown that when thimerosal is removed entirels: from vaccines, the rates of autism do not

decline. In fact, those rates continue to increase at the same pace as before (Fombonne, 2008). If,

-58~

as postulated by Dr Greenland, there was a two-fold increase in the risk of a type of autism

occurring in 10% of the cases, which is due to thimerosal containing vaccines, one should expect a

fall of about 10% in the rates of autism following the discontinuation of thimerosal in vaccines

(assuming complete vaccine coverage in the child population). No such fall has been documented.

In fact, in two of the studies, the levels of thimerosal exposure before its elimination from vaccines

were at U.S. levels (Schechter & Grether, 2008; Fombonne et al., 2006b). Furthermore, the rates of

regression in ASDs in studies of children who were exposed to the U.S. levels ofthimerosal are

about 20% (Lord et al., 2004). This is no different from rates that have been reported in British

studies where thimerosal levels were lower (Taylor et al, 2002; Fombonne & Chakrabarti, 2001 c;

Fombonne et al., 200.4). There is no evidence that the proportion of regressive autism has

decreased after the discontinuation ofthimerosal in vaccines.

129. In sum, Dr Greenland makes in his report a methodological remark that is

technically correct but remains purely hypothetical, has no empirical grounding to support it, and

ultimately lacks the essential pre-requisites that would make it a workable scientific hypothesis.

Jordan King

130. Jordan King was born on September 29, 1997. He was the product of an

uncomplicated pregnancy. His mother, then age thirty-six, presented with a spontaneous

membrane rupture, and during delivery had a high fever (101 degrees) treated with antibiotics.

Jordan’s birth weight was 71bs, 14oz, and his Apgar scores were 8 and 8. He passed his two-week

and two-month developmental check-ups with his doctor, Dr Lauren Roberts, without problems

(exhibit 2, page 34).

131. Sleeping and bowel problems were noted at his four-month check-up with

dry stools and constipation and (difficult to read) sleeping descriptions. At six months of age

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(exhibit 2, page 33), sleeping problems were still reported, but he seemed to be developing well,

generally. Jordan had an episode of diarrhea, in August 1998, at eleven months of age (four

months after his last immunization series). He passed his one-year check-up well, and his doctor

noted that he babbled and understood well.

132. At sixteen months of age, Jordan had an infectious episode that was

investigated in the Emergency Room of the Providence Portland Medical Center (exhibit 3, pages

77 and 78), with a resulting diagnosis of a viral syndrome.

133. Dr Roberts saw Jordan, on March 17, 1999, at the age of 17½ months, for

coughing and a febrile episode. His mother’s description indicated that Jordan seemed lethargic.

Dr Roberts noted that Jordan was "sleepy now but wandering/exploring drawers" (exhibit 2, page

27).

134. On July 1, 1999, at the age of twenty-one months, Dr Reagan evaluated

Jordan for another viral illness. Dr Reagan’s notes indicated that Jordan appeared "actually

surprisingly open-minded and moderately comfortable" (exhibit 2, page 25).

135. On October 25, 1999, at almost twenty-five months of age, Dr Roberts

identified significant developmental concerns with Jordan, including the fact that he did not talk at

all; he made a lot of noise, such as grunts and humming on and on; and he had no language. Dr.

Roberts noted possible autism, which required a developmental evaluation, and indicated that

Jordan had previously used single words (exhibit 2, page 23).

136. Jordan received the normal immunization schedule recommended at the

time, including MMR at one year of age, and the complement of other vaccines.

137. Jordan was referred to the Pediatric Development and Rehabilitation~

Program, in November 1999, at twenty-six months of age. His mother completed a questionnaire

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and indicated her concern that Jordan did not speak at all. She further indicated that Jordan babbled

normally and used single words around one year of age and then stopped. She also noted that he

did not relate well to non-family members, preferred to play alone in group settings, seemed to be

annoyed by the loud babbling of his baby sister, and did not come when called (exhibit 7, page 9).

138. Jordan’s regression is difficult to assess. He apparently started to use single

words around his first birthday, although the exact age varies from nine months (exhibit 1, page 41)

to thirteen months (exhibit 8, page 168). The extent of his vocabulary at that age is difficult to

evaluate, although examples ("shoes," "juice") are found in some records. There is not much

evidence that his language progressed between the ages of 12 and 18 months. In fact, his

pediatrician’s notes are remarkable for their lack of reference to language development during that -

period. It is then asserted that Jordan lost his skills in June 1999, around twenty months of age.

Although his parents indicated he was a "normal child until around age 20 months" (exhibit 8, page

189), they wrote to Dr Budden that they noticed the first changes in Jordan at 18 months of age

when he "would not stay with the group and instead would wander over to the boom box and play

with the buttons" (exhibit 8, page 189). This corresponds to the age (17.5 months) at which Dr

Roberts’s notes indicated that Jordan is "sleepy now but wandering/exploring drawers" (exhibit 2,

page 27). Although it appears likely that Jordan lost the few language skills that he had acquired (a

few single words), it is probable that his development was not normal before the loss at 18 or 20

months of age, and before the emergence of clear autistic symptoms. His language failed to

progress between 12 and 18 months of age, and according to his parents’ comparative comments

with regard to his sister’s behavior, Jordan "was never a babbler. His vocalisations were fairly

limited compared to her articulations." (exhibit 8, page 189).

-61 -

139. Jordan was evaluated with the Rossetti Infant-Toddler Language Scale at two

years, three months of age, which documented a delay in language skills and social skills, and

raised the possibility of a PDD spectrum diagnosis. He was subsequently referred for speech

therapy. A second language assessment at twenty-nine months of age with the Preschool Language

Scale (PLS)-3 documented significant delays in expressive (age equivalent: 3 months) and

receptive (age equivalent: 7 months) language skills. (exhibit 8, pages 168-169).

140. On January 25, 2000, at the age of 2 years, 3 months, Jordan had a cognitive

assessment with the Battelle Developmental Inventory, which showed a standard score of 65

.(percentile 1), corresponding to an age equivalent of 14 months (for adaptive skills) (exhibit 8, page

101). He obtained nearly identical results on personal social skills. In motor skills, he had a

standard score of 82 for gross motor skills and 75 for fine motor skills.

141. Jordan was diagnosed with autism in early 2000 after the speech and

language evaluation and his first contact with the Early Intervention Programs of Portland. The

diagnosis was later confirmed by a pediatric psychiatrist, Dr Stubbs, and by Dr Budden, a

pediatrician, in August 2000 (exhibit 8, pages 56-60).

142. As soon Jordan received an autism diagnosis, the records indicate that his

parents understandably began an active search for a biomedical explanation for their son’s

difficulties that spanned different organs and mechanisms, including pancreatic deficiency,

digestive problems, abnormal metabolism, and toxic exposures (exhibit 2, pages 18 and 21). Like

many parents who are searching for a cause, Jordan’s parents requested that he be seen by a

naturopath, Dr Pamela Jeanne, and by Dr John Green, who both began treating Jordan. It is

important to note that multiple investigations were performed that led to negative or inconsistent

results, and to Jordan being prescribed many supplements and medications that were administered

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at a very early stage. Jordan’s parents also started him on a gluten-free and casein-free diet in

January 2000. Equally important is the fact that an early intervention program using speech

therapy and, later, behavioral techniques was started in early 2000.

143. There were, therefore, multiple interventions that were immediately

implemented that involved both behavioral and educational measures, and a range of biomedical

treatments. The constant changing of biomedical treatments together with the fact that behavioral

treatments were taking place at the same time renders it impossible to evaluate the efficacy of each

component of Jordan’s multifaceted treatment programme.

144.

.

145.

146.

147.

.

148.

- 63 -

149.

150.

.

151.

152.

153.

154.

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155.

- 65 -

156.

157.

158.

159.

- 66 -

160. In

William Mead

161. William Mead was born on May 5, 1998, at St. Vincent Hospital at thirty-

nine weeks’ gestation. His birth weight was 91bs 4oz, and his Apgar scores were 8 and 9. His

parents were 36 and 37 years of age when William was born. Newborn screening test results were

normal. There were no complications during the neonatal period.

162. There is a positive family history for arthritis, thyroid dysfunction, asthma,

and allergies on the maternal side, and of cancer and alcohol problems on the paternal side.

163. William passed his check-up visits at 4 and 6 months with no problems

identified besides intermittent and benign colds or upper respiratory infections.

164. He was given the normal immunization schedule, and received MMR and

Varivax at 1 year, 5 days of age.

165. The first developmental concerns appear in the medical notes at William’s 2-

year check-up on May 15, 2000. The doctor mentioned "no speech" (exhibit 1, page 22). The

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doctor further comments that William "hears well," ~acts on language," "responds to commands,"

"plays ball, rolling it back etc." (exhibit 1, page 22). There is also a mention that there are "no

words," and that William "does not point or know body parts." The doctor recommends "tloor

time" for mother and William, 10 minutes at a time, and suggests a reassessment in 3 or 4 months if

there is no verbal progress (exhibit 1, page 22).

166. On August 29, 2000, at approximately 28 months of age, it is noted that

William is not talking, and an audiology referral is obtained. William underwent an audiological

examination on September 25, 2000, and the examiner observed that William did not make eye

contact or engage in play. In the weeks that followed, he was referred to the Autism Clinic for a

developmental assessment.

167. On November 28, 2000, at 2½ years of age, an evaluation by Dr Alvan Pang

confirmed the autism diagnosis. Based on parental reports, the developmental history now

indicates that the symptoms occurred after the MMR immunization at 1 year of age with

gastrointestinal illness followed rapidly by deterioration in social, motor, and intellectual skills. On

that date, William’s parents had already started him on nutritional supplements, including DMG.

William. had also been started on a casein- and gluten-free diet, and his parents wanted to pursue

hypotheses regarding heavy metal toxicity, immune dysfunction, candida overgrowth, and similar

issues.

168. In a letter dated January 17, 2001 (exhibit 4, pages 42-43), Dr Pang indicates

a different developmental history with a dramatic decrease in verbal abilities and loss of language

noted by the parents in August 2000 (i.e., at the age of approximately 27 months). This account of

language loss in the summer of 2000 is further documented in a letter by William’s father to Dr

John Green, dated November 30, 2000 (exhibit 4, page 26).

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169. In the same letter from January 2001, an account is given of William

attending, during the 1999-2000 academic year, a "Mommy and Me" school program where

William’s teachers noted lack of age appropriate social or cooperative play, and the fact that

William was becoming increasingly isolated. The director of this program asked that William be

withdrawn from the program and placed more appropriately elsewhere. This suggests anomalies in

the social and play domains that occurred before the alleged loss of language in August 2000, and

probably before the two-year medical check-up in which William’s speech delay was first noted as

a.concern.

170. An assessment performed at the Autism Clinic of the Oregon Health

Sciences University, in December 2000, included a summary of William’s speech and language

assessment performed previously at 29 months of age. This showed receptive language at the

equivalent of 9 months of age, and expressive language skills at the equivalent of 12 months of age.

On the re-evaluation two months later with the same test, William showed an improvement from 2

to 5 months in his language skills. In addition, William began applied behavioral analysis training

atBuiding Bridges for 30 hours per week in late 2000.

171. In the psychiatry report (exhibit 4, page 35), Williams’s parents give an

account of absolutely normal development up to 18 months of age, at which point William would

have already received his MMR vaccination. I note that the MMR vaccination was given on May

10, 1999 (at 12 months of age). This parental report is, therefore, inaccurate. Moreover, the

description given of William’s development before age 18 months is improbable -- that of a child

having three- to four-word phrases, pointing at objects, making good eye contact, and even having

a vocabulary of 60 words that was subsequently completely lost.

172. During the same evaluation, on December 12, 2000, Dr Stubbs, a child

psychiatrist, reports a different developmental history with loss of words occurring in August 2000

(at 27 months of age) (exhibit 4, page 35). Dr Stubbs confirmed the diagnosis of Autistic Disorder

(exhibit 4, pages 37-38).

173. In the fall of 2000, William was receiving different types of intervention,

including up to 30 hours per week of applied behavioral analysis using the discreet trial method,

and a series of biomedical treatments that more or less followed the DAN! protocol (DMG, amino

acids, cod liver oil, melatonin, glutation, vitamin B5, and other compounds).

174. The evaluation of William’s possible regression and loss of language skills is

made very difficult because of highly inconsistent reports in his medical file. According to his

pediatrician’s notes, the first concerns are noted at age two in the form of speech delay. There is no

evidence from the previous visits during William’s second year of life that he had developed any

speech, or that he had developed and then lost speech. If he had indeed developed up to 60 words

and subsequently lost those words at 18 months, this would certainly have been reported in the

pediatrician’s file, which is not the case. Further, there are inconsistencies in the dates of the

supposed regression. Based on parental accounts, professionals report either a loss of skills

occurring at 18 months in a child who was developing normally until then, or they report language

loss occurring at 27 months, in August 2000. Because it is highly implausible that William would

have had 60 words at 18 months of age and then lost them, and because the connection the parents

make with the MMR vaccination at 18 months of age is wrong according to the medical records

(MMR was given at one year of age), it is more likely that the parents recognized changes and

autistic symptoms in William during the summer of 2000. However, it is unclear how much speech

he might have lost at this time. Even if some loss of words could be established at 27 months of

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age, it is clear that William’s prior development was not normal. His pediatrician noted speech

delay at two years of age, and William was asked to leave a daycare program during the 1999-2000

school year, most likely before his second birthday. It is, therefore, likely that William’s first

autistic symptoms occurred in the form of a lack of speech development during his second year of

life, associated with delays in play and social skills, which became gradually more evident to both

the parents and the pediatrician, who identified them for the first time at age two. It is difficult to

establish whether or not loss of skills occurred at 27 months of age. If it did, the loss of skills

occurred after the onset of William’s first autistic symptoms.

175. In 2001, William continued to be treated by a combination of behavioral

techniques and multiple compounds prescribed by Dr Green that were changed frequently. He also

received IVIG, auditory integration therapy, chelation therapy, and secretin infusion, to name only

a few interventions. It is impossible to draw any conclusions about the efficacy of interventions or

the causes of William’s autism from this medical history.

Dr Mumper’s Reports

176. I have reviewed all available medical records of Jordan King, William Mead,

and . I have also read the three reports of the petitioners’ expert, Dr Elizabeth

Mumper.

177. In her three reports, Dr Mumper makes a number of statements that are not

substantiated in the scientific literature or in the clinical experience. Some examples of faulty

reasoning are as follows:

a. Dr Mumper ignores all the published scientific evidence that does not

support her "causal" theory. In particular, she makes no mention of the range of controlled

epidemiological studies that have all failed to show an increase in the risk of autism in

-71 -

children following exposure to various doses of thimerosal received as part of the routine

immunization schedule in the United States during the 1990s. The fact that controlled

studies in human subjects have consistently yielded negative results is not evaluated by Dr

Mumper. Moreover, the fact that rates of autism have not declined following the removal

of thimerosal in childhood vaccines in Scandinavia (Madsen et al, 2004; Stehr-Green et al,

2003), in Canada (Fombonne et al, 2006b), and now in the U.S. (Schechter & Grether,

2008) is even not considered. As Dr Mumper appears to be a proponent of the hypothesis

of an autism epidemic triggered by childhood vaccines

King’s report, page 7, paragraph 6), it is puzzling that she pays no attention to

population-based, well-controlled epidemiological studies and time trends that contradict it.

b. Dr Mumper fails to examine alternative causal explanations for the Mead,

King, and children’s autism. This is particularly apparent when she wrongly

asserts that the absence of signs of dysmorphology or the presence of normal results for

genetic testing regarding karyotype, the MECP2 gene, argue for a role of an environmental

factor in these three cases. This statement is incorrect and fails to recognize that if the

presence of dysmorphic signs or of a genetic abnormality, when found, positively points at

early abnormal embryogenic development or abnormal genetic background, the absence of

such abnormalities does not rule out prenatal onset or a genetic cause of autism. This is

well-illustrated in recent genetic findings (Weiss et al., 2008; Autism Genome Project,

2007) where microdeletions and microduplications have been found on several

chromosomes which account for up to 10% or 15% of autism cases. Such abnormalities

were unknown two years ago because techniques to detect them were just not available.

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c. The failure to account for alternative causal explanations is also obvious in

the lack of attention Dr Mumper paid to alternative environmental exposures. Most

obviously, if one assumes for purposes of argument that exposure to ethylmercury can

induce autism, Dr Mumper cannot rule out other sources of mereury to which William

Mead, Jordan King, and w were exposed. In fact, in the case of Jordan

King, Dr Mumper admits that his medical records indicate he ate a lot of tuna and that he

was exposed to other neurotoxicants. These other environmental exposures presumably fit

within her view of an environmental cause of Jordan’ s autism.

d. Dr Mumper misinterprets scientific studies in an attempt to buttress her lack

of evidence for causation. For example, she repeatedly quotes studies by Mundy et al.,

Dawson et al., Fein et al., and Kelley et ak that describe optimal outcomes in children

diagnosed with autism or PDD in preschool years. Dr Mumper argues these studies indicate

that environmental components are demonstrated by these positive outcomes. This reflects

an ignorance of the natural history of autism which is, at times, associated with spectacular

improvements, irrespective of interventions received and of the causal mechanisms

involved. Secondly, in none of the studies mentioned has the author referred to vaccination

theories or mercury-induced autism. If anything, these authors, in their discussion of these

good trajectories, argued that early detection, which is now taking place, and access to early

intensive behavioral interventions, are the likely factors accounting for these positive

outcomes.

e. Dr Mumper further misinterprets the supposed effects of chelation therapy.

She wrongly infers that because autistic children occasionally excrete higher amounts of

mercury following chelation, this is somehow proof that these children suffer from mercury

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overburden that could bethe cause of their autism. This is plainly wrong. In these

observations collected in the course of clinical practice, there is not even baseline pre-

chelation mercury excretion data that could help interpret the post-treatment excretion

figure. Secondly, it is clear from the literature that administration of a chelating agent to

anyone (autistic or not) will be followed by increased excretion of mercury. This does not

mean that the mercury is a cause of any health problem in the subject undergoing chelation.

To provide a simple analogy, if autistic children were treated with diuretics, they would

certainly display increased urine output. It would not, however, follow from this

observation that the children’s autism resulted from fluid retention or renal insufficiency.

f. Dr Mumper makes statements supporting the implementation of so-called

treatments, although there is no evidence of their efficacy. The only evidence from which

she quotes is that of her own clinical experience. It must be noted, however, that the

clinical experience of most autism specialists contradicts Dr Mumper’s opinions. There are

standards to establish the efficacy of interventions in medicine through the use of controlled

studies, particularly using methodology known as randomized, double-blind, placebo-

controlled clinical trials. Most of the interventions that Dr Mumper supports and claims to

have been efficacious in the treatment of Jordan King w, and William

Mead have not been subjected to any scientifically rigorous testing for their efficacy.

Moreover, some of these interventions, such as secretin infusion, have a history worth

noting. After the report of three cases of apparent improvements in autistic

symptomatology following secretin infusion, multiple families and practitioners began

using this treatment for autistic children. Parents and practitioners reported improvements,

and a number of people believed that an efficacious therapy had been found. Yet when

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secretin was rigorously tested for its efficacy in three separate randomized clinical trials,

with evaluators being blind to treatment status, none of the studies showed any beneficial

value to secretin. This history, and others like it, suggest that the clinical experience, or the

informal observations made by families or practitioners, can often be seriously misleading.

None of the methods supported by Dr Mumper has been shown, through scientifically

reliable testing, to be efficacious in the treatment of autism.

178. The histories of autistic symptoms in Jordan Kin kow, and

William Mead are remarkably comparable to those medical records or histories of children whom I

have assessed in settings where exposure to thimerosal through the immunization schedule was

either lower than in the U.S. (as in the U.K.) or nil (as in Quebec).

Conclusion

179. It is my opinion, to a reasonable degree of scientific and medical certainty,

that thimerosal-containing vaccines neither caused nor contributed to Jordan King’s, William

Mead’s, and ’s autism. The claim that there is an autism epidemic caused by

thimerosal-containing vaccines is unfounded, without reliable scientific support, and is not

generally accepted in the autism community. There is no reliable scientific or medical basis to

support the conclusion that there is an association or a causal relationship between thimerosal-

containing vaccines and ASDs, and the evidence favors rejection of such a causal relationship.

There is no basis for the claim that a subgroup of individuals with regressive autism and previously

normal development represents a valid subtype and that it would have a unique association with

thimerosal-containing vaccines that would not have been detected in existing studies. In fact, the

replicated observation that the discontinuation of thimerosal from childhood vaccines in several

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countries was not followed by a downward trend in rates of autism argues clearly for a lack of an

association.

Eric Fombonne, M.D., F.R.C.Psych

Date: February 25th 2008

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o

°

°

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